BRAF (gene)

8/9/2019 BRAF (gene)

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BRAF (gene)

BRAF is a human gene that makes a protein called B-

Raf. The gene is also referred to as proto-oncogene

B-Raf and v-Raf murine sarcoma viral oncogene ho-

molog B, while the protein is more formally known as

serine/threonine-protein kinase B-Raf.[2][3]

The B-Raf protein is involved in sending signals inside

cells, which are involved in directing cell growth. In

2002, it was shown to be faulty (mutated) in some human

cancers.[4]

Certain other inherited BRAF mutations cause birth de-fects.

Drugs that treat cancers driven by BRAF mutations have

been developed. Two of these drugs, vemurafenib[5] and

dabrafenib are approved by FDA for treatment of late-

stage melanoma. Vemurafenib was the first drug to come

out of fragment-based drug discovery.

1 Function

Gene Regulation

CellProliferation

Apoptosis

Survival Factors

(e.g., IGF1)

Chemokines,Hormones,

Transmitters

(e.g., interleukins,serotonin, etc.)

Growth Factors

(e.g., TGFα, EGF)

Extracellular

Matrix

Integrins

Dishevelled

cdc42

Fyn/ShcGrb2/SOS

Ras

Raf

MEK

FAK

Src

MEKK MA PK MKK

GSK-3β

APC

β-catenin

TCF

Myc: Mad:

Max Max ERK JNKs

JunFos

β-catenin:TCF

CREB

PKA

Adenylatecyclase

PLC

PKC

NF-κB

IκB

STAT3,5

Bcl-xL

Cytochrome C

Caspase 9

Bcl-2

Caspase 8

FADD

FasR

Bad

AbnormalitySensor Bim

Mt Bax

ARF

mdm2

p53

Death factors(e.g. FasL, Tnf)

Cytokines(e.g., EPC)

JAKs

C y t o k i n e R e c e p t o r

Wnt

Hedgehog

CycIDCDK4Rb

E2F

CyclE p27

p21

CDK2

RTK

GPCR

RTK

G-ProteinPI3K

Akt

Akkα

Glip16

p15

F r i z z l e d

P a t c h e d

S M O

Overview of signal transduction pathways involved in apoptosis .

The role of Raf proteins, like B-Raf is indicated in the center.

B-Raf is a member of the Raf kinase family of growth

signal transduction protein kinases. This protein plays

a role in regulating the MAP kinase/ERKs signaling

pathway, which affects cell division, differentiation, and

secretion.[6]

2 Structure

B-Raf is a 766-amino acid, regulated signal transduction

serine/threonine-specific protein kinase. Broadly speak-

ing, it is composed of three conserved domains char-

acteristic of the Raf kinase family: conserved region

1 (CR1), a Ras-GTP-binding[7] self-regulatory domain,

conserved region 2 (CR2), a serine-rich hinge region, and

conserved region 3 (CR3), a catalytic protein kinase do-

main that phosphorylates a consensus sequence on pro-

tein substrates.[8] In its active conformation, B-Raf forms

dimers via hydrogen-bonding and electrostatic interac-

tions of its kinase domains.[9]

2.1 CR1

Conserved region 1 autoinhibits B-Raf’s kinase do-

main (CR3) so that B-Raf signaling is regulated rather

than constitutive.[8] Residues 155–227[10] make up the

Ras-binding domain (RBD), which binds to Ras-GTP’s

effector domain to release CR1 and halt kinase inhibi-

tion. Residues 234–280 comprise a phorbol ester/DAG-

binding zinc finger motif that participates in B-Raf mem-

brane docking after Ras-binding.[10][11]

2.2 CR2

Conserved Region 2 (CR2) provides a flexible linker that

connects CR1 and CR3 and acts as a hinge.

2.3 CR3

Conserved Region 3 (CR3), residues 457–717,[10] makes

up B-Raf’s enzymatic kinase domain. This largely con-

served structure[12] is bi-lobal, connected by a short hinge

region.[13] The smaller N-lobe (residues 457–530) is pri-

marily responsible for ATP binding while the larger C-

lobe (residues 535–717) binds substrate proteins.[12] The

active site is the cleft between the two lobes, and the cat-

alytic Asp576 residue is located on the C-lobe, facing the

inside of this cleft.[10][12]

2.3.1 Subregions

P-Loop

The P-loop of B-Raf (residues 464–471) stabilizes the

non-transferable phosphate groups of ATP during en-

zyme ATP-binding. Specifically, S467, F468, and G469

backbone amides hydrogen-bond to the β-phosphate ofATP to anchor the molecule. B-Raf functional mo-

tifs have been determined by analyzing the homology of

1

https://en.wikipedia.org/wiki/Proto-oncogenehttps://en.wikipedia.org/wiki/Amidehttps://en.wikipedia.org/wiki/Glycinehttps://en.wikipedia.org/wiki/Phenylalaninehttps://en.wikipedia.org/wiki/Serinehttps://en.wikipedia.org/wiki/Phosphatehttps://en.wikipedia.org/wiki/Walker_motifshttps://en.wikipedia.org/wiki/Aspartic_acidhttps://en.wikipedia.org/wiki/Enzyme_substrate_(biology)https://en.wikipedia.org/wiki/C-terminushttps://en.wikipedia.org/wiki/Adenosine_triphosphatehttps://en.wikipedia.org/wiki/N-terminushttps://en.wikipedia.org/wiki/Zinc_fingerhttps://en.wikipedia.org/wiki/Diacylglycerolhttps://en.wikipedia.org/wiki/Phorbolhttps://en.wikipedia.org/wiki/Effector_(biology)https://en.wikipedia.org/wiki/Ras_subfamilyhttps://en.wikipedia.org/wiki/Enzyme_inhibitorhttps://en.wikipedia.org/wiki/Hydrogen_bondhttps://en.wikipedia.org/wiki/Consensus_sequencehttps://en.wikipedia.org/wiki/Phosphorylationhttps://en.wikipedia.org/wiki/Protein_kinasehttps://en.wikipedia.org/wiki/Serinehttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Ras_subfamilyhttps://en.wikipedia.org/wiki/Raf_kinasehttps://en.wikipedia.org/wiki/Protein_domainhttps://en.wikipedia.org/wiki/Serine/threonine-specific_protein_kinasehttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Amino_acidhttps://en.wikipedia.org/wiki/Cellular_differentiationhttps://en.wikipedia.org/wiki/Cell_divisionhttps://en.wikipedia.org/wiki/MAPK/ERK_pathwayhttps://en.wikipedia.org/wiki/MAPK/ERK_pathwayhttps://en.wikipedia.org/wiki/Extracellular_signal-regulated_kinaseshttps://en.wikipedia.org/wiki/Mitogen-activated_protein_kinasehttps://en.wikipedia.org/wiki/Protein_kinasehttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Raf_kinasehttps://en.wikipedia.org/wiki/Apoptosishttps://en.wikipedia.org/wiki/Fragment-based_drug_discoveryhttps://en.wikipedia.org/wiki/Dabrafenibhttps://en.wikipedia.org/wiki/Vemurafenibhttps://en.wikipedia.org/wiki/Cancershttps://en.wikipedia.org/wiki/Mutationhttps://en.wikipedia.org/wiki/Cell_growthhttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Proto-oncogenehttps://en.wikipedia.org/wiki/Proteinhttps://en.wikipedia.org/wiki/Gene


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2 3 ENZYMOLOGY

Figure 1: Inactive conformation of B-Raf kinase (CR3) domain.

P-Loop (orange) hydrophobic interactions with activation loop

(gray) residues that stabilize the inactive kinase conformation are

shown with sticks. F595 (red) blocks the hydrophobic pocket

where the ATP adenine binds (yellow). D576 (orange) is shown

as part of the catalytic loop (magenta). Figure modified from

PDB id 1UWH.

PKA analyzed by Hanks and Hunter to the B-Raf kinase

domain.[12]

Nucleotide-Binding Pocket

V471, C532, W531, T529, L514, and A481 form a hy-

drophobic pocket within which the adenine of ATP is

anchored through Van der Waals attractions upon ATP

binding.[12][14]

Catalytic Loop

Residues 574–581 compose a section of the kinase do-

main responsible for supporting the transfer of the γ-

phosphate of ATP to B-Raf’s protein substrate. In par-

ticular, D576 acts as a proton acceptor to activate the

nucleophilic hydroxyl oxygen on substrate serine or thre-

onine residues, allowing the phosphate transfer reactionto occur mediated by base-catalysis.[12]

DFG Motif

D594, F595, and G596 compose a motif central to B-

Raf’s function in both its inactive and active state. In

the inactive state, F595 occupies the nucleotide-binding

pocket, prohibiting ATP from entering and decreasing

the likelihood of enzyme catalysis.[9][14][15] In the active

state, D594 chelates the divalent magnesium cation that

stabilizes the β- and γ-phosphate groups of ATP, orient-

ing the γ-phosphate for transfer.[12]

Activation Loop

Residues 596–600 form strong hydrophobic interactions

with the P-loop in the inactive conformation of the ki-

nase, locking the kinase in its inactive state until the acti-

vation loop is phosphorylated, destabilizing these interac-

tions with the presence of negative charge. This triggers

the shift to the active state of the kinase. Specifically,

L597 and V600 of the activation loop interact with G466,

F468, and V471 of the P-loop to keep the kinase domain

inactive until it is phosphorylated.[13]

3 Enzymology

B-Raf is a serine/threonine-specific protein kinase. As

such, it catalyzes the phosphorylation of serine and

threonine residues in a consensus sequence on target pro-

teins by ATP, yielding ADP and a phosphorylated protein

as products.[12] Since it is a highly regulated signal trans-

duction kinase, B-Raf must first bind Ras-GTP before be-

coming active as an enzyme.[11] Once B-Raf is activated,

a conserved protein kinase catalytic core phosphorylates

protein substrates by promoting the nucleophilic attack

of the activated substrate serine or threonine hydroxyl

oxygen atom on the γ-phosphate group of ATP through

bimolecular nucleophilic substitution.[12][16][17][18]

3.1 Activation

3.1.1 Relieving CR1 autoinhibition

The kinase (CR3) domain of human Raf kinases is in-

hibited by two mechanisms: autoinhibition by its ownregulatory Ras-GTP-binding CR1 domain and a lack

of post-translational phosphorylation of key serine and

tyrosine residues (S338 and Y341 for c-Raf) in the CR2

hinge region. During B-Raf activation, the protein’s

autoinhibitory CR1 domain first binds Ras-GTP’s effector

domain to the CR1 Ras-binding domain (RBD) to re-

lease the kinase CR3 domain like other members of the

human Raf kinase family. The CR1-Ras interaction is

later strengthened through the binding of the cysteine-

rich subdomain (CRD) of CR1 to Ras and membrane

phospholipids.[8] Unlike A-Raf and C-Raf, which must

be phosphorylated on hydroxyl-containing CR2 residuesbefore fully releasing CR1 to become active, B-Raf is

constituitively phosphorylated on CR2 S445.[19] This al-

lows the negatively charged phosphoserine to immedi-

ately repel CR1 through steric and electrostatic interac-

tions once the regulatory domain is unbound, freeing the

CR3 kinase domain to interact with substrate proteins.

3.1.2 CR3 domain activation

After the autoinhibitory CR1 regulatory domain is re-

leased, B-Raf’s CR3 kinase domain must change to its

ATP-binding active conformer before it can catalyze pro-tein phosphorylation. In the inactive conformation, F595

of the DFG motif blocks the hydrophobic adenine bind-

https://en.wikipedia.org/wiki/Adeninehttps://en.wikipedia.org/wiki/Hydrophobehttps://en.wikipedia.org/wiki/Conformational_isomerismhttps://en.wikipedia.org/wiki/Adenosine_triphosphatehttps://en.wikipedia.org/wiki/Protein_kinasehttps://en.wikipedia.org/wiki/C-Rafhttps://en.wikipedia.org/wiki/ARAFhttps://en.wikipedia.org/wiki/Phospholipidhttps://en.wikipedia.org/wiki/Cell_membranehttps://en.wikipedia.org/wiki/Cysteinehttps://en.wikipedia.org/wiki/Raf_kinasehttps://en.wikipedia.org/wiki/Effector_(biology)https://en.wikipedia.org/wiki/Enzyme_induction_and_inhibitionhttps://en.wikipedia.org/wiki/Tyrosinehttps://en.wikipedia.org/wiki/Posttranslational_modificationhttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Ras_subfamilyhttps://en.wikipedia.org/wiki/Regulatory_enzymeshttps://en.wikipedia.org/wiki/Enzyme_induction_and_inhibitionhttps://en.wikipedia.org/wiki/Raf_kinasehttps://en.wikipedia.org/wiki/Bimolecular_nucleophilic_substitutionhttps://en.wikipedia.org/wiki/Alpha_and_beta_carbonhttps://en.wikipedia.org/wiki/Hydroxylhttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Ras_subfamilyhttps://en.wikipedia.org/wiki/Protein_kinasehttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Adenosine_diphosphatehttps://en.wikipedia.org/wiki/Adenosine_triphosphatehttps://en.wikipedia.org/wiki/Consensus_sequencehttps://en.wikipedia.org/wiki/Threoninehttps://en.wikipedia.org/wiki/Serinehttps://en.wikipedia.org/wiki/Serine/threonine-specific_protein_kinasehttps://en.wikipedia.org/wiki/Cationhttps://en.wikipedia.org/wiki/Magnesiumhttps://en.wikipedia.org/wiki/Divalenthttps://en.wikipedia.org/wiki/Chelationhttps://en.wikipedia.org/wiki/Acid_catalysishttps://en.wikipedia.org/wiki/Nucleophilehttps://en.wikipedia.org/wiki/Base_(chemistry)https://en.wikipedia.org/wiki/Aspartic_acidhttps://en.wikipedia.org/wiki/Alaninehttps://en.wikipedia.org/wiki/Leucinehttps://en.wikipedia.org/wiki/Threoninehttps://en.wikipedia.org/wiki/Tryptophanhttps://en.wikipedia.org/wiki/Cysteinehttps://en.wikipedia.org/wiki/Valinehttps://en.wikipedia.org/wiki/Protein_kinase_A


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3.3 Inhibitors 3

ing pocket while activation loop residues form hydropho-

bic interactions with the P-loop, stopping ATP from ac-

cessing its binding site. When the activation loop is phos-

phorylated, the negative charge of the phosphate is unsta-

ble in the hydrophobic environment of the P-loop. As a

result, the activation loop changes conformation, stretch-

ing out across the C-lobe of the kinase domain. In thisprocess, it forms stabilizing β-sheet interactions with the

β6 strand. Meanwhile, the phosphorylated residue ap-

proaches K507, forming a stabilizing salt bridge to lock

the activation loop into place. The DFG motif changes

conformation with the activation loop, causing F595 to

move out of the adenine nucleotide binding site and into

a hydrophobic pocket bordered by the αC and αE he-

lices. Together, DFG and activation loop movement upon

phosphorylation open the ATP binding site. Since all

other substrate-binding and catalytic domains are already

in place, phosphorylation of the activation loop alone ac-

tivates B-Raf’s kinase domain through a chain reactionthat essentially removes a lid from an otherwise-prepared

active site.[13]

3.2 Mechanism of catalysis

Figure 2: Base-catalyzed nucleophilic attack of a ser-

ine/threonine substrate residue on the γ-phosphate group of ATP.

Step 1: chelation of secondary magnesium ion by N581 and de-

protonation of substrate Ser/Thr by D576. Step 2: nucleophilic

attack of activated substrate hydroxyl on ATP γ-phosphate. Step

3: magnesium complex breaks down and D576 deprotonates.

Step 4: release of products.

To effectively catalyze protein phosphorylation via the bi-

molecular substitution of serine and threonine residues

with ADP as a leaving group, B-Raf must first bind ATPand then stabilize the transition state as the γ-phosphate

of ATP is transferred.[12]

3.2.1 ATP binding

B-Raf binds ATP by anchoring the adenine nucleotide

in a nonpolar pocket (yellow, Figure 1) and orient-

ing the molecule through hydrogen-bonding and electro-

static interactions with phosphate groups. In addition to

the P-loop and DFG motif phosphate binding describedabove, K483 and E501 play key roles in stabilizing non-

transferable phosphate groups. The positive charge on

the primary amine of K483 allows it to stabilize the nega-

tive charge on ATP α- and β-phosphate groups when ATP

binds. When ATP is not present, the negative charge of

the E501 carboxyl group balances this charge.[12][13]

3.2.2 Phosphorylation

Once ATP is bound to the B-Raf kinase domain, D576 of

the catalytic loop activates a substrate hydroxyl group, in-

creasing its nucleophilicity to kinetically drive the phos-

phorylation reaction while other catalytic loop residues

stabilize the transition state.(Figure 2). N581 chelates

the divalent magnesium cation associated with ATP to

help orient the molecule for optimal substitution. K578

neutralizes the negative charge on the γ-phosphate group

of ATP so that the activated ser/thr substrate residue

won't experience as much electron-electron repulsion

when attacking the phosphate. After the phosphate group

is transferred, ADP and the new phosphoprotein are

released.[12]

3.3 Inhibitors

Since constitutively active B-Raf mutants commonly

cause cancer (see Clinical Significance) by excessively

signaling cells to grow, inhibitors of B-Raf have been

developed for both the inactive and active confor-

mations of the kinase domain as cancer therapeutic

candidates.[13][14][15]

3.3.1 Sorafenib

BAY43-9006 (Sorafenib, Nexavar)is a V600E mutant B-Raf and C-Raf inhibitor approved by the FDA for the

treatment of primary liver and kidney cancer. Bay43-

9006 disables the B-Raf kinase domain by locking the en-

zyme in its inactive form. The inhibitor accomplishes this

by blocking the ATP binding pocket through high-affinity

for the kinase domain. It then binds key activation loop

and DFG motif residues to stop the movement of the ac-

tivation loop and DFG motif to the active conformation.

Finally, a trifluoromethyl phenyl moiety sterically blocks

the DFG motif and activation loop active conformation

site, making it impossible for the kinase domain to shift

conformation to become active.

[13]

The distal pyridyl ring of BAY43-9006 anchors in the

hydrophobic nucleotide-binding pocket of the kinase N-

https://en.wikipedia.org/wiki/Pyridinehttps://en.wikipedia.org/wiki/Affinity_(pharmacology)https://en.wikipedia.org/wiki/Protein_kinasehttps://en.wikipedia.org/wiki/Renal_cell_carcinomahttps://en.wikipedia.org/wiki/Hepatocellular_carcinomahttps://en.wikipedia.org/wiki/Food_and_Drug_Administrationhttps://en.wikipedia.org/wiki/C-Rafhttps://en.wikipedia.org/wiki/Mutanthttps://en.wikipedia.org/wiki/Sorafenibhttps://en.wikipedia.org/wiki/Carboxylhttps://en.wikipedia.org/wiki/Aminehttps://en.wikipedia.org/wiki/Nonpolarhttps://en.wikipedia.org/wiki/Transition_statehttps://en.wikipedia.org/wiki/Leaving_grouphttps://en.wikipedia.org/wiki/Adenosine_diphosphatehttps://en.wikipedia.org/wiki/Alpha_helixhttps://en.wikipedia.org/wiki/Alpha_helixhttps://en.wikipedia.org/wiki/Beta_sheet


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4 4 CLINICAL SIGNIFICANCE

Figure 3: B-Raf kinase domain locked in the inactive conforma-

tion by bound BAY43-9006. Hydrophobic interactions anchor

BAY43-9006 in the ATP binding site while urea group hydrogen-bonding traps D594 of the DFG motif. The BAY43-9006 trifluo-

romethyl phenyl ring further prohibits DFG motif and activation

loop movement to the active confermer via steric blockage.

lobe, interacting with W531, F583, and F595. The hy-

drophobic interactions with catalytic loop F583 and DFG

motif F595 stabilize the inactive conformation of these

structures, decreasing the likelihood of enzyme activa-

tion. Further hydrophobic interaction of K483, L514,

and T529 with the center phenyl ring increase the affinity

of the kinase domain for the inhibitor. Hydrophobic

interaction of F595 with the center ring as well de-creases the energetic favorability of a DFG conforma-

tion switch further. Finally, polar interactions of BAY43-

9006 with the kinase domain continue this trend of in-

creasing enzyme affinity for the inhibitor and stabilizing

DFG residues in the inactive conformation. E501 and

C532 hydrogen bond the urea and pyridyl groups of the

inhibitor respectively while the urea carbonyl accepts a

hydrogen bond from D594’s backbone amide nitrogen to

lock the DFG motif in place.[13]

The trifluoromethyl phenyl moiety cements the thermo-

dynamic favorability of the inactive conformation when

the kinase domain is bound to BAY43-9006 by stericallyblocking the hydrophobic pocket between the αC and αE

helices that the DFG motif and activation loop would in-

habit upon shifting to their locations in the active confor-

mation of the protein.[13]

3.3.2 Vemurafenib

PLX4032 (Vemurafenib) is a V600 mutant B-Raf in-

hibitor approved by the FDA for the treatment of late-

stage melanoma.[9] Unlike BAY43-9006, which inhibits

the inactive form of the kinase domain, Vemurafenib

inhibits the active “DFG-in” form of the kinase,[14][15]firmly anchoring itself in the ATP-binding site. By in-

hibiting only the active form of the kinase, Vemurafenib

Figure 4: Structures of Vemurafenib (right) and its precursor,

PLX 4720 (left), two inhibitors of the active conformation of the

B-Raf kinase domain

selectively inhibits the proliferation of cells with unregu-

lated B-Raf, normally those that cause cancer.

Since Vemurafenib only differs from its precursor,

PLX4720, in a phenyl ring added for pharmacokinetic

reasons,[15] PLX4720’s mode of action is equivalent to

Vemurafenib’s. PLX4720 has good affinity for the ATP

binding site partially because its anchor region, a 7-

azaindole bicyclic, only differs from the natural adeninethat occupies the site in two places where nitrogen atoms

have been replaced by carbon. This enables strong in-

termolecular interactions like N7 hydrogen bonding to

C532 and N1 hydrogen bonding to Q530 to be pre-

served. Excellent fit within the ATP-binding hydropho-

bic pocket (C532, W531, T529, L514, A481) increases

binding affinity as well. Ketone linker hydrogen bonding

to water and difluoro-phenyl fit in a second hydrophobic

pocket (A481, V482, K483, V471, I527, T529, L514,

and F583) contribute to the exceptionally high binding

affinity overall. Selective binding to active Raf is ac-

complished by the terminal propyl group that binds to

a Raf-selective pocket created by a shift of the αC he-

lix. Selectivity for the active conformation of the ki-

nase is further increased by a pH-sensitive deprotonated

sulfonamide group that is stabilized by hydrogen bonding

with the backbone peptide NH of D594 in the active state.

In the inactive state, the inhibitor’s sulfonamide group in-

teracts with the backbone carbonyl of that residue instead,

creating repulsion. Thus, Vemurafenib binds preferen-

tially to the active state of B-Raf’s kinase domain.[14][15]

4 Clinical significance

Mutations in the BRAF gene can cause disease in two

ways. First, mutations can be inherited and cause birth

defects. Second, mutations can appear later in life and

cause cancer, as an oncogene.

Inherited mutations in this gene cause

cardiofaciocutaneous syndrome, a disease charac-

terized by heart defects, mental retardation and a

distinctive facial appearance.[20]

Acquired mutations in this gene have been found in can-

cers, including non-Hodgkin lymphoma, colorectal can-

cer, malignant melanoma, papillary thyroid carcinoma,non-small-cell lung carcinoma, and adenocarcinoma of

the lung.[6]

https://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lunghttps://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lunghttps://en.wikipedia.org/wiki/Non-small-cell_lung_carcinomahttps://en.wikipedia.org/wiki/Papillary_thyroid_cancerhttps://en.wikipedia.org/wiki/Melanomahttps://en.wikipedia.org/wiki/Colorectal_cancerhttps://en.wikipedia.org/wiki/Colorectal_cancerhttps://en.wikipedia.org/wiki/Non-Hodgkin_lymphomahttps://en.wikipedia.org/wiki/Cardiofaciocutaneous_syndromehttps://en.wikipedia.org/wiki/Oncogenehttps://en.wikipedia.org/wiki/Carbonylhttps://en.wikipedia.org/wiki/Sulfonamide_(medicine)https://en.wikipedia.org/wiki/Ketonehttps://en.wikipedia.org/wiki/Bicyclic_moleculehttps://en.wikipedia.org/wiki/Indolehttps://en.wikipedia.org/wiki/Pharmacokineticshttps://en.wikipedia.org/wiki/Phenylhttps://en.wikipedia.org/wiki/Cancerhttps://en.wikipedia.org/wiki/Sorafenibhttps://en.wikipedia.org/wiki/Melanomahttps://en.wikipedia.org/wiki/Food_and_Drug_Administrationhttps://en.wikipedia.org/wiki/Mutanthttps://en.wikipedia.org/wiki/Vemurafenibhttps://en.wikipedia.org/wiki/Amidehttps://en.wikipedia.org/wiki/Carbonylhttps://en.wikipedia.org/wiki/Ureahttps://en.wikipedia.org/wiki/Ureahttps://en.wikipedia.org/wiki/Affinity_(pharmacology)https://en.wikipedia.org/wiki/Phenyl


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4.2 BRAF inhibitors in the clinic 5

The V600E mutation of the BRAF gene has been associ-

ated with hairy cell leukemia in numerous studies and has

been suggested for use in screening for Lynch syndrome

to reduce the number of patients undergoing unnecessary

MLH1 sequencing.[21]

4.1 Mutants

More than 30 mutations of the BRAF gene associated

with human cancers have been identified. The frequency

of BRAF mutations varies widely in human cancers, from

more than 80% in melanomas and nevi, to as little as 0–

18% in other tumors, such as 1–3% in lung cancers and

5% in colorectal cancer.[22] In 90% of the cases, thymine

is substituted with adenine at nucleotide 1799. This leadsto valine (V) being substituted for by glutamate (E) at

codon 600 (now referred to as V600E) in the activa-

tion segment that has been found in human cancers.[23]

This mutation has been widely observed in papillary

thyroid carcinoma, colorectal cancer, melanoma and

non-small-cell lung cancer.[24][25][26][27][28][29][30] BRAF-

V600E mutation are present in 57% of Langerhans

cell histiocytosis patients.[31] The V600E mutation is a

likely driver mutation in 100% of cases of hairy cell

leukaemia.[32] High frequency of BRAF V600E muta-

tions have been detected in ameloblastoma, a benign but

locally infiltrative odontogenic neoplasm.[33] The V600E

mutation may also be linked, as a single-driver mutation

(a genetic 'smoking gun') to certain cases of papillary

craniopharyngioma development.[34]

Other mutations which have been found are R461I,

I462S, G463E, G463V, G465A, G465E, G465V,

G468A, G468E, N580S, E585K, D593V, F594L,

G595R, L596V, T598I, V599D, V599E, V599K,

V599R, V600K, A727V, etc. and most of these mu-

tations are clustered to two regions: the glycine-rich P

loop of the N lobe and the activation segment and flank-

ing regions.[1] These mutations change the activation seg-

ment from inactive state to active state, for example in

the previous cited paper it has been reported that the

aliphatic side chain of Val599 interacts with the phenyl

ring of Phe467 in the P loop. Replacing themedium sized

hydrophobic Val side chain with a larger and charged

residue as found in human cancer(Glu, Asp, Lys, or Arg)

would be expected to destabilize the interactions that

maintain the DFG motif in an inactive conformation, so

flipping the activation segment into the active position.

Depending on the type of mutation the kinase activity to-

wards MEK may also vary. Most of the mutants stimu-

late enhanced B-Raf kinase activity toward MEK. How-

ever, a few mutants act through a different mechanism be-

cause although their activity toward MEK is reduced, theyadopt a conformation that activates wild-type C-RAF,

which then signals to ERK.

4.1.1 BRAF-V600E

• BRAF V600E is a determinant of sensitivity to

proteasome inhibitors. Vulnerability to proteasome

inhibitors is dependent on persistent BRAF signal-

ing, because BRAF-V600E blockade by PLX4720

reversed sensitivity to carfilzomib in BRAF-mutantcolorectal cancer cells. Proteasome inhibition might

represent a valuable targeting strategy in BRAF

V600E-mutant colorectal tumors.[35]

4.2 BRAF inhibitors in the clinic

As mentioned above, some pharmaceutical firms are de-

veloping specific inhibitors of mutated B-raf protein for

anticancer use because BRAF is a well-understood, high

yield target.[14][36] Vemurafenib (RG7204 or PLX4032),

licensed by the US Food and Drug Administration as

Zelboraf for the treatment of metastatic melanoma in Au-

gust 2011, is the current state-of-the-art example for why

active B-Raf inhibitors are being pursued as drug can-

didates. Vemurafenib is biochemically interesting as a

mechanism to target cancer due to its high efficacy and

selectivity.[9] In Phase II[37] and Phase III[38] clinical tri-

als, B-Raf not only increased metastatic melanoma pa-

tient chance of survival but raised the response rate to

treatment from 7-12% to 53% inthe sameamount of time

compared to the former best chemotherapeutic treatment:

dacarbazine. In spite of the drug’s high efficacy, 20% of

tumors still develop resistance to the treatment. In mice,

20% of tumors become resistant after 56 days. [39] Whilethe mechanisms of this resistance are still disputed, some

hypotheses include the overexpression of B-Raf to com-

pensate for high concentrations of Vemurafenib[39] and

upstream upregulation of growth signaling.[40]

More general B-raf inhibitors include GDC-0879, PLX-

4720, Sorafenib Tosylate. dabrafenib, LGX818

5 Interactions

BRAF (gene) has been shown to interact with:

• AKT1,[41]

• C-Raf,[42]

• HRAS,[43][44] and

• YWHAB.[45][46]

6 References

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roid carcinomas are derived from papillary carci-

nomas due to BRAF and p53 mutations”. Cancer

103 (11): 2261–8. doi:10.1002/cncr.21073. PMID

15880523.

• Karbowniczek M, Henske EP (2006). “The role

of tuberin in cellular differentiation: are B-Raf

and MAPK involved?". Ann N Y Acad Sci 1059

(1): 168–73. doi:10.1196/annals.1339.045. PMID

16382052.

• Ciampi R, Nikiforov YE (2007). “RET/PTC re-

arrangements and BRAF mutations in thyroid tu-

morigenesis”. Endocrinology 148 (3): 936–41.

doi:10.1210/en.2006-0921. PMID 16946010.

• Espinosa AV, Porchia L, Ringel MD(2007). “Targeting BRAF in thyroid can-

cer”. British Journal of Cancer 96 (1): 16–20.

doi:10.1038/sj.bjc.6603520. PMC 2360215.

PMID 17179987.

8 External links

• Allanson, Judith E; Roberts, Amy E (2011-08-04).

Noonan Syndrome. NBK1124. In Pagon RA, Bird

TD, Dolan CR et al., eds. (1993–). GeneReviews™

[Internet]. Seattle WA: University of Washington,Seattle. Check date values in: |date= (help)

• Rauen, Katherine A (2012-09-06).

Cardiofaciocutaneous Syndrome. NBK1186.

In GeneReviews

• Gelb, Bruce D; Tartaglia, Marco (2010-11-16).

LEOPARD Syndrome. NBK1383. In GeneReviews

• “BRAF gene”. NCI Dictionary of Cancer Terms.

Retrieved 2007-11-25.

• Finding faults in BRAF — Cancer Research UKblog post about the discovery of cancer-causing

BRAF mutations (incl video)

http://scienceblog.cancerresearchuk.org/2009/08/24/high-impact-science-%25E2%2580%2593-finding-faults-in-braf/http://www.cancer.gov/dictionary?CdrID=561325https://en.wikipedia.org/wiki/BRAF_(gene)#CITEREFGeneReviewshttp://www.ncbi.nlm.nih.gov/books/NBK1383/https://en.wikipedia.org/wiki/BRAF_(gene)#CITEREFGeneReviewshttp://www.ncbi.nlm.nih.gov/books/NBK1186/https://en.wikipedia.org/wiki/Help:CS1_errors#bad_datehttp://www.ncbi.nlm.nih.gov/books/n/gene/TOC/http://www.ncbi.nlm.nih.gov/books/n/gene/TOC/http://www.ncbi.nlm.nih.gov/books/NBK1124/https://www.ncbi.nlm.nih.gov/pubmed/17179987https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360215https://en.wikipedia.org/wiki/PubMed_Centralhttps://dx.doi.org/10.1038%252Fsj.bjc.6603520https://en.wikipedia.org/wiki/Digital_object_identifierhttps://en.wikipedia.org/wiki/British_Journal_of_Cancerhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360215https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360215https://www.ncbi.nlm.nih.gov/pubmed/16946010https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1210%252Fen.2006-0921https://en.wikipedia.org/wiki/Digital_object_identifierhttps://en.wikipedia.org/wiki/Endocrinology_(journal)https://www.ncbi.nlm.nih.gov/pubmed/16382052https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1196%252Fannals.1339.045https://en.wikipedia.org/wiki/Digital_object_identifierhttps://en.wikipedia.org/wiki/Ann_N_Y_Acad_Scihttps://www.ncbi.nlm.nih.gov/pubmed/15880523https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1002%252Fcncr.21073https://en.wikipedia.org/wiki/Digital_object_identifierhttps://en.wikipedia.org/wiki/Cancer_(journal)https://www.ncbi.nlm.nih.gov/pubmed/15488754https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1016%252Fj.ccr.2004.09.022https://en.wikipedia.org/wiki/Digital_object_identifierhttps://en.wikipedia.org/wiki/Cancer_Cellhttps://www.ncbi.nlm.nih.gov/pubmed/10931830https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1074%252Fjbc.M003327200https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pubmed/17353931https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948https://en.wikipedia.org/wiki/PubMed_Centralhttps://dx.doi.org/10.1038%252Fmsb4100134https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847948https://www.ncbi.nlm.nih.gov/pubmed/7706312https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1074%252Fjbc.270.13.7644https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pubmed/9154803https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC232157https://en.wikipedia.org/wiki/PubMed_Centralhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC232157https://www.ncbi.nlm.nih.gov/pmc/articles/PMC232157https://www.ncbi.nlm.nih.gov/pmc/articles/PMC232157https://www.ncbi.nlm.nih.gov/pubmed/11325826https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pubmed/10869359https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1074%252Fjbc.M004371200https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pubmed/21107323https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143360https://en.wikipedia.org/wiki/PubMed_Centralhttps://dx.doi.org/10.1038%252Fnature09626https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143360https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143360https://www.ncbi.nlm.nih.gov/pubmed/23302800https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.1038%252Fnature11814https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pubmed/21639808https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296https://en.wikipedia.org/wiki/PubMed_Centralhttps://dx.doi.org/10.1056%252FNEJMoa1103782https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296https://www.ncbi.nlm.nih.gov/pubmed/22356324https://en.wikipedia.org/wiki/PubMed_Identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724515https://en.wikipedia.org/wiki/PubMed_Centralhttps://dx.doi.org/10.1056%252FNEJMoa1112302https://en.wikipedia.org/wiki/Digital_object_identifierhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724515https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724515


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9

This article incorporates public domain material from the

U.S. National Cancer Institute document “Dictionary of

Cancer Terms”. This article incorporates text from the

United States National Library of Medicine , which is in

the public domain.

https://en.wikipedia.org/wiki/Public_domainhttps://en.wikipedia.org/wiki/United_States_National_Library_of_Medicinehttp://www.cancer.gov/dictionaryhttp://www.cancer.gov/dictionaryhttps://en.wikipedia.org/wiki/National_Cancer_Institutehttps://en.wikipedia.org/wiki/Copyright_status_of_work_by_the_U.S._government


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10 9 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

9 Text and image sources, contributors, and licenses

9.1 Text

• BRAF (gene) Source: http://en.wikipedia.org/wiki/BRAF_(gene)?oldid=659842841 Contributors: The Anome, Ronz, Nurg, Rich Farm-

brough, Arcadian, Rjwilmsi, Ground Zero, RussBot, RDBrown, Niels Olson, Eastlaw, Patho~enwiki, Agathman, Alaibot, Hb2019, Nono64,

Nbauman, Boghog, Rod57, Andrew Su, ProteinBoxBot, LeadSongDog, Fratrep, ClueBot, Poptop43, Vini 175, Lihmwiki, Ts4079, Dthom-

sen8, Addbot, DOI bot, Quercus solaris, Anypodetos, Kmcital, Citation bot, Arcendet, Citation bot 1, Yeast2Hybrid, Inferior Olive, Duu-

uuudeHaha, Amkilpatrick, DarthTrevis, Ahaduzzamanmunna, H3llBot, Nhevitt, Earnur~enwiki, HenryScow, BG19bot, BattyBot, Chris-

Gualtieri, Intronic2, PC-XT, Liz, Anrnusna, Monkbot, Hheikinh and Anonymous: 29

9.2 Images

• File:B-Raf_Phosphorylation_Mechanism.png Source: http://upload.wikimedia.org/wikipedia/commons/2/2e/B-Raf_

Phosphorylation_Mechanism.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Nhevitt

• File:BRAF_Kinase_Inactive.png Source: http://upload.wikimedia.org/wikipedia/commons/5/5a/BRAF_Kinase_Inactive.png License:

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• File:PDB_1uwh_EBI.jpg Source: http://upload.wikimedia.org/wikipedia/commons/b/b7/PDB_1uwh_EBI.jpg License: Public domain

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1uwh/summary Original artist: Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute

• File:PDB_1uwj_EBI.jpg Source: http://upload.wikimedia.org/wikipedia/commons/5/58/PDB_1uwj_EBI.jpg License: Public domainContributors: http://www.ebi.ac.uk/pdbe-srv/view/images/entry/1uwj600.png, displayed on http://www.ebi.ac.uk/pdbe-srv/view/entry/

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• File:PDB_2fb8_EBI.png Source: http://upload.wikimedia.org/wikipedia/commons/a/a6/PDB_2fb8_EBI.png License: Public domain

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2fb8/summary Original artist: Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute

• File:Protein_BRAF_PDB_1uwh.png Source: http://upload.wikimedia.org/wikipedia/commons/a/af/Protein_BRAF_PDB_1uwh.png

License: CC BY-SA 3.0 Contributors: Own work Original artist: Emw

• File:Signal_transduction_pathways.svg Source: http://upload.wikimedia.org/wikipedia/commons/b/b0/Signal_transduction_

pathways.svg License: CC BY-SA 3.0 Contributors: http://en.wikipedia.org/wiki/File:Signal_transduction_v1.png Original artist:

cybertory

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cense: CC BY-SA 3.0 Contributors: Own work Original artist: Nhevitt

• File:Vemurafenib.png Source: http://upload.wikimedia.org/wikipedia/commons/0/0e/Vemurafenib.png License: CC BY-SA 3.0 Con-

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