RAF1

Protein RAF1

Identifiers
HUGO:RAF1
v-raf-1 murine leukemia viral oncogene homolog 1
HUGO:RAF1, HGNC:9829, ENTREZ:5894??, GENECARDS:GC03M012625, UNIPROT:P04049
HUGO:RAF1 HGNC:9829 ENTREZ:5894 UNIPROT:P04049
HUGO:RAF1 HGNC:9829 ENTREZ:5894 UNIPROT:P04049 GENECARDS:RAF1 REACTOME:58255 KEGG:5894 ATLASONC:RAF1ID42032ch3p25 WIKI:RAF1

Maps_Modules
HMC:AVOIDING_IMMUNE_DESTRUCTION
Adaptive Immune Response / TCR_SIGNALING
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
EMT Senescence / MITOCHONDRIA_OXIDATIVE_STRESS
HMC:RESISTING_CELL_DEATH
Regulated Cell Death / APOPTOSIS
Regulated Cell Death / MOMP_REGULATION
Regulated Cell Death / NECROPTOSIS
Innate Immunity / IMMUNOSTIMULATORY_CORE_PATHWAYS
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / MAPK
Survival / WNT_NON_CANONICAL

References
PMID:11532940
PMID:24027568 PMID:14764585
PMID:9069260
Inactive RAF1 is associated in the cytoplasm with YWHAB.
YWHAB binds to RAF1 via the Ser259 phosphorylation site.
This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured.
RAF1 contains an additional RAS-binding domain (RBD).
NATURAL_KILLER
PMID:15516985, PMID:12566895
HRAS activates MEK/ERK pathway via RAF phosphorylation in NK cells.
Ras functions asan adapter that binds to Raf kinases.
Raf can activate both MEK1 and MEK2 (also called MKK1 and MKK2)
Active KRas (on late endosomes) recruits Raf1 (C-Raf) to elicit a MODULE:MAPK signalling pathway.
Raf1 MEK1/2 and ERK1/2 may act in the outer side of the Golgi apparatus and attenuate proliferation.
PMID:19289794 PMID:19565474

RAF1|closed@Cytosol

References
em_emtc_emtc_re383( EMT Senescence ):
Negative feedback: MAPK1/ERK2 phosphorylates RAF1 on Ser 29, 43, 289, 296, 301, 642, generating an inactive kinase.
PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A.

References
em_emtc_emtc_re387( EMT Senescence ):
PMID:9069260
Activated HRAS (GTP bound forn) is associated with the plasma membrane.
Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site.
RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD).
RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD.
YWHAB has been displaced from S259 may now bind its higher affinity S621 site.
This stabilises an OPEN RAF1 conformation that is catalytically active.
Active and open RAF1 binds to RAS via both CRD and RBD domains.
An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341.
This Tyrosine phosphorylation serves to further stabilise the active OPEN RAF1 conformation.
While the kinase has not been definitively identified, SRC is a plausible candidate. RAF1 interacts with SRC and co-immunoprecipates with SRC-FYN.
PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A.
Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: S338, Y374 and T491
em_emtc_emtc_re853( EMT Senescence ):
PMID:10712905
PMID:9823899
PAK3 phosphorylates RAF1 at S338 and upregulates RAF1

References
em_emtc_emtc_re853( EMT Senescence ):
PMID:9069260
Activated HRAS (GTP bound forn) is associated with the plasma membrane.
Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site.
RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD).
RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD.
YWHAB has been displaced from S259 may now bind its higher affinity S621 site.
This stabilises an OPEN RAF1 conformation that is catalytically active.
Active and open RAF1 binds to RAS via both CRD and RBD domains.
An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341.
This Tyrosine phosphorylation serves to further stabilise the active OPEN RAF1 conformation.
While the kinase has not been definitively identified, SRC is a plausible candidate. RAF1 interacts with SRC and co-immunoprecipates with SRC-FYN.
PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A.
Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: S338, Y374 and T491
PMID:10712905
PMID:9823899
PAK3 phosphorylates RAF1 at S338 and upregulates RAF1
em_emtc_emtc_re388( EMT Senescence ):
PMID:7565670
Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
em_emtc_emtc_re1616( EMT Senescence ):
PMID:12175651
PMID:10826997
PMID:12767520
PMID:19030972
PMID:16931767
PMID:21540285
PMID:12444011
IGFfamily exhibits anti-apoptotic activity.
Three IGF1R-induced anti-apoptotic pathways:
1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation.
Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death.
Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death.
2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD.
3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5)

RAF1|S_pho|closed@Cytosol

References
em_emtc_emtc_re1616( EMT Senescence ):
PMID:12175651
PMID:10826997
PMID:12767520
PMID:19030972
PMID:16931767
PMID:21540285
PMID:12444011
IGFfamily exhibits anti-apoptotic activity.
Three IGF1R-induced anti-apoptotic pathways:
1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation.
Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death.
Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death.
2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD.
3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5)

RAF1@Cytosol

Maps_Modules
HMC:RESISTING_CELL_DEATH
Regulated Cell Death / APOPTOSIS
Regulated Cell Death / MOMP_REGULATION
Regulated Cell Death / NECROPTOSIS

References
rc_re1420( Regulated Cell Death ):
PMID:8929532
in vitro RAF1:BCL2 interaction
in 293, overexpression of BCL2 induces relocalization of RAF1-GFP to mitochondria
in vitro phosphorylation of BAD by RAF1
in 293T, over-expression of a mitochondria-targeted version of RAF1 induces phosphorylation of BAD (controls: plasma membrane targeted RAF1, kinase dead mutant)
BCL2 over-expression targets RAF1 kinase domain-GFP to mitochondria
mitochondria-targeted RAF1 (deleted for Ras binding domain) potentiates BCL2 anti-apoptotic activity in 32D.3 exposed to staurosporine or upon IL-3 withdrawal

RAF1@Cytoplasm

References
su_mpk1_mpk1_re86( Survival ):
The internalised GPCR receptor will finally be recycled into the cell membrane or be sent to lysosome for degradation (not modelled).
PMID:19565474
su_mpk1_mpk1_re193( Survival ):
MEK is continuously dephosphorylated by PP2A (PPP2CA) whose activity is stimulated by P38: P38 activity increases the physical association between PP2A and MEK/ERK complex. A direct interaction between P38 and ERK has been proposed as a mechanism to inhibit ERK phosphorylation. AP-1 mediated gene expression inhibits ERK phosphorylation.
PMID:18039929
su_mpk1_mpk1_re21( Survival ):
Active KRas (on late endosomes) recruits Raf1 (C-Raf) to elicit a MODULE:MAPK signalling pathway.
RasGTP and Sur-8 allow dephosphorylation of N-ter 14-3-3 binding site of Raf (not modelled) and thus its recruitment.
PMID:19289794 PMID:17496910
su_mpk1_mpk1_re55( Survival ):
RasGTP and Sur-8 allow dephosphorylation of N-ter 14-3-3 binding site of Raf and thus its recruitment.
PMID:17496910
su_mpk1_mpk1_re62( Survival ):
The component kinases of the ERK cascade Raf-1 MEK and ERK assemble using beta-ARRESTIN as a scaffold and leading to activation of ERK. Endocytosis of these receptor/beta-ARRESTIN complexes by clathrin-coated pits results in the targeting of activated ERK to endosomal vesicles.
The beta-ARRESTIN occupied receptor undergoes internalisation into early endosomes. At the early endosome stage beta-ARRESTIN recruits both MEK1/2 and ERK1/2 and is likely to facilitate their activation upon GPCR stimulation.
PMID:11226259 PMID:19565474
su_mpk1_mpk1_re102( Survival ):
When Ras assumes an active conformation through binding of GTP a subpopulation of the Raf-1 (C-Raf) protein molecules in cells translocates from the cytosol to the plasma membrane via interaction with P21ras (not modelled).
PMID:8929532
su_mpk1_mpk1_re283( Survival ):
PKCalpha directly phosphorylates and activates Raf-1.
PMID:8321321
su_wnc1_s_wnc4_re22( Survival ):
c-Raf; MEK1/2; ERK1/2;HRAS
PMID:19906679
TGF-b1 in airway smooth muscle cells
PMID:21908588

RAF1|pho@Mitochondria

References
su_mpk1_mpk1_re103( Survival ):
BCL2 protein can target Raf-1 (C-Raf) to mitochondria.
PMID:8929532
su_mpk1_mpk1_re118( Survival ):
A mitochondrial pool of Raf-1 (C-RAF) molecules which do not activate MEK reportedly exert their prosurvival effects upstream of cytochrome c release by phosphorylating the pro-apoptotic Bcl-2 family member BAD. Phosphorylation of BAD results in its translocation to the cytosol and ultimately in the inhibition of cytochrome c release.
PMID:12107820

RAF1|pho@Cytoplasm

References
su_mpk1_mpk1_re283( Survival ):
PKCalpha directly phosphorylates and activates Raf-1.
PMID:8321321
su_mpk1_mpk1_re186( Survival ):
MLK3 and MLK2 two MAP3Ks of JNK pathway can interact with RAC1 in a GTP-dependent manner.
MEKK2 and MEKK3 can activate JNK P38 and ERK pathways
MLK3 has the potential to positively regulate the ERK / MAPK pathway by directly phosphorylating and activating MEK.
PMID:11274345 PMID:12738796