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FLASH GENE

Symbol

RAF1

contributors: mct - updated : 24-12-2018

HGNC name	v-raf-1 murine leukemia viral oncogene homolog 1
HGNC id	9829

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	LEOPS2 Leopard syndrome 2 NS5 Noonan syndrome 5
Location	3p25.2      Physical location : 12.625.101 - 12.705.700
Synonym name	RAF proto-oncogene serine/threonine protein kinase
	oncogene RAF1
Synonym symbol(s)	MIL, KRAF, C-RAF, Raf-1, CRAF, NS5
EC.number	2.7.11.1

DNA

TYPE	functioning gene
SPECIAL FEATURE	head to head
STRUCTURE	80.60 kb     17 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	pter - D3S1442 , D3S1443 , D13S1444 , D3S17 - D3S18 - VHL VHL - D3S1317 - [D3S601 - D3S1038 ],ATP2B2 - D3S587 - D3S720 - D3S1250 - D3S732 - RAF1 - D3S651 - D3S656 - D3S1110 - D3S1255 - THRB THRB - cen
Text	see PTPRG

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002880 17 - 3291 NP_002871 72.9 648 - 1992 1639773

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic thymus       highly Cardiovascular heart       highly Respiratory lung       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	serine/threonine kinase, RAF-like RAS binding domain (RBD)
	one zinc dependant phorbol-ester and DAG binding domain
	three CR, conserved region (CR1, AA 61-192, CR2 AA 251-266 and CR3 AA 333-625)
	a CRD, cysteine-rich domain
	a minimal 24 AAs long PEBP1 binding domain in the N-region

HOMOLOGY

interspecies

homolog to murine leukemia viral oncogene 1 v-raf-1

Homologene

FAMILY	protein kinase superfamily
	TKL Ser/Thr protein kinase family
	RAF subfamily

CATEGORY

enzyme , protooncogene

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria,outer
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	translocate to mitochondria and thereby protect cells from stress-mediated apoptosis

basic FUNCTION	regulator of cellular proliferation, differentiation, and apoptosis
	effector kinase of Ras, crucial integrator in the mitogenic cytoplasmic kinase MAPK pathway
	participating to the RAS-RAF-MEK-ERK- pathway in promoting tumorigenesis
	downstream effector of RAS signaling in the MAPK pathway
	may induce cell proliferation through hypermethylation of tumor suppressor gene CDKN2A
	STK3 serves as a hub to integrate biological outputs of the RAF1 and AKT pathways
	its activity is essential to establish the balance between cell proliferation and death in neuroepithelial otic precursors, and for otic neuron differentiation and axonal growth at the acoustic-vestibular ganglion
	plays a unique role in mediating KRAS signaling and makes it a suitable target for therapeutic intervention
	elevated RAF1 mitochondrial translocation induced the increased anti-apoptotic effect and subsequently promoted HBx-mediated hepatocarcinogenesis
	major downstream target of several growth factors that promote proliferation and survival of many cell types, including the pancreatic beta cells
	RAF1 signaling is essential for the regulation of basal insulin transcription and the supply of releasable insulin

CELLULAR PROCESS	cell life, differentiation
	cell life, proliferation/growth
	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

amplification of RAF1/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition

a component	components of the two MAPK cascades, MAP3K5-MAP2K4-MAPK10 and RAF1-MAPK1-MAP2K1 interacting with arrestins
	in the heart, melusin forms a supramolecular complex with the proto-oncogene RAF1, MAPKK1/2 and MAPK1/MAPK3

INTERACTION

DNA

RNA

small molecule

protein	phosphorylating MEKs (MAP2Ks)
	NFKB through MEKK1 activation
	interacting with TC21 for activation and translocation to plasma membrane
	interacting with CNKSR1 (mediates Src-dependent tyrosine phosphorylation and activation of RAF1)
	interaction with PEBP1 (binds to RAF1 interfering with binding of the MEK substrate and potentially also RAF1 activation)
	physically associated with the IL2RB (p75) in T-cell blasts (following tyrosine phosphorylation, enzymatically active RAF1 dissociates from the IL2 receptor and translocates into the cytosol)
	potent regulator of RAF1 activity and may control RAF1 dependent signaling at mitochondria
	interacting with BIRC4
	binding of 14-3-3 proteins to the N terminus of RAF1 attenuates the Ras-RAF-MAPK pathway by sequestering RAF1 in the cytoplasm
	association of BRAF with RAF1 induces the activation of RAF1
	ARRB2-RAF1 interaction is enhanced by receptor binding
	RAF1 and ADRBK1 are direct interaction partners of PEBP1 (PEBP1 dimer formation controls its target switch from RAF1 to ADRBK1)
	DIRAS3 interacts with RAF1 to specifically suppress the activating phosphorylations on MEK and ERK, thus restricting migration of non-cancer cells
	MAP2K1 activates RAF1 through a Ras-independent mechanism
	PDE8A is a physiological regulator of RAF1 signaling in some cells
	PDE8A exerts part of its control of T cell function through RAF1 kinase signaling pathway

cell & other

REGULATION

Other	ubiquitinated after its binding to XIAP
	regulated by HSPA5 (may stabilize RAF1 to maintain mitochondrial permeability and thus protect cells from ER stress-induced apoptosis

ASSOCIATED DISORDERS

corresponding disease(s)

LEOPS2 , NS5

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       in-frame oncogenic fusion between SRGAP3 and RAF1 in Pilocytic astrocytomas constitutional     --other   dysfunction (expression) of the FGFR1, SOS1 and RAF1 genes is involved in the development of unilateral or bilateral cryptorchidism tumoral fusion       with LRCH3, CTNNA1, GOLGA4, CTDSPL, MAP4, PRKAR2A in melanomas tumoral fusion       LRRFIP2-RAF1 fusion identified in an acral melanoma

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular valvulopathy   modulating the RAF1Ser(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway, as Noonan or Leopard syndrome cancer     excellent molecular target for anticancer therapy

ANIMAL & CELL MODELS