protein
RAF proto-oncogene serine/threonine-protein kinase
Gene
RAF1
Organism
Homo sapiens(9606)
Length
648 aa
Mass
73,052 Da
RAF1 (RAF proto-oncogene serine/threonine-protein kinase) is a regulatory serine/threonine kinase that serves as a critical link between membrane-associated Ras GTPases and the MAPK/ERK signaling cascade (UniProt: P04049). It acts as a molecular switch controlling cell fate decisions including proliferation, differentiation, apoptosis, and survival through sequential phosphorylation of downstream kinases MAP2K1/MEK1, MAP2K2/MEK2, and the extracellular signal-regulated kinases ERK1 and ERK2. RAF1 also regulates additional cellular processes including NF-κB activation, wound healing, and apoptosis through both cytoplasmic and mitochondrial signaling.
RAF1 mutations are associated with multiple developmental and cardiac disorders. These include Noonan syndrome 5 (NS5), characterized by short stature, facial dysmorphic features, congenital heart defects, and intellectual disability; LEOPARD syndrome 2 (LPRD2), featuring lentigines and conduction abnormalities; and dilated cardiomyopathy (CMD1NN) with ventricular dysfunction (UniProt: P04049). These conditions highlight RAF1's critical role in normal cardiovascular and skeletal development.
RAF1 is classified as a SFARI syndromic candidate gene (SFARI Cat S), indicating evidence for association with autism in the context of genetic syndromes, though primary manifestations involve developmental and cardiac phenotypes rather than autism as the primary feature.
Generated from the curated entity record below. May contain errors — verify against source links.
Genetic Evidence · ASD
Source: SFARI Gene database · gene.sfari.org
Related Publications
Browse all →Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
Ruzzo Elizabeth K et al.Cell2019PMID 31398340Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
Guo Hui et al.Molecular autism2018PMID 30564305Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
C Yuen Ryan K et al.Nature neuroscience2017PMID 28263302Identification of common genetic risk variants for autism spectrum disorder.
Grove Jakob et al.Nature genetics2019PMID 30804558Synaptic, transcriptional and chromatin genes disrupted in autism.
De Rubeis Silvia et al.Nature2014PMID 25363760
Function
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation
Disease associations
Noonan syndrome 5NS5
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.
LEOPARD syndrome 2LPRD2
A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
Cardiomyopathy, dilated, 1NNCMD1NN
A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
Sources
Last updated 5/6/2026, 5:24:45 AM