RAF1

Protein RAF1 map

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

Maps_Modules
 EMT  map  / EMT_REGULATORS  map
 Apoptosis  map  / MOMP_REGULATION  map
 Survival  map  / MAPK  map
 Survival  map  / WNT_NON_CANONICAL  map

References
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).
Active KRas (on late endosomes) recruits Raf1 (C-Raf) to elicit a MODULE:MAPK map 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@Cytoplasm

References
e_re383( EMT  map ):
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.

RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​open@Cytoplasm

References
e_re387( EMT  map ):
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
e_re853( EMT  map ):
PMID:10712905
PMID:9823899
PAK3 phosphorylates RAF1 at S338 and upregulates RAF1

RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Cytoplasm

References
e_re853( EMT  map ):
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
e_re388( EMT  map ):
PMID:7565670
Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
e_re1616( EMT  map ):
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@Cytoplasm

References
e_re383( EMT  map ):
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.

RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Mitochondria

References
e_re1616( EMT  map ):
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@Cytoplasm

References
a_re1420( Apoptosis  map ):
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|​pho@Mitochondria

References
s_mpk1_re103( Survival  map ):
BCL2 protein can target Raf-1 (C-Raf) to mitochondria.
PMID:8929532
s_mpk1_re118( Survival  map ):
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
s_mpk1_re283( Survival  map ):
PKCalpha directly phosphorylates and activates Raf-1.
PMID:8321321
s_mpk1_re186( Survival  map ):
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  map pathway by directly phosphorylating and activating MEK.
PMID:11274345 PMID:12738796


Modifications:
In compartment: Cytoplasm
  1. RAF1@Cytoplasm map

  2. RAF1|​pho@Cytoplasm map
  3. RAF1|​closed@Cytoplasm map
  4. RAF1|​S_pho|​closed@Cytoplasm map
  5. RAF1|​S259_pho|​S621_pho|​S_pho|​closed@Cytoplasm map
  6. RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​open@Cytoplasm map
  7. RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Cytoplasm map

In compartment: Mitochondria

  1. RAF1|​pho@Mitochondria map

  2. RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Mitochondria map

Participates in complexes:
In compartment: Cytoplasm

  1. RAF1|​S259_pho|​S621_pho|​S_pho|​closed:​YWHAB@Cytoplasm map

  2. GTP:​RAF1|​S259_pho|​S621_pho|​S_pho|​open:​YWHAB@Cytoplasm map
  3. GTP:​HRAS:​RAF1|​S259_pho|​S621_pho|​S_pho|​closed@Cytoplasm map

In compartment: Early Endosomes

  1. ERK*|​pho|​pho:​GPCR*:​GRK*:​MEK*|​pho|​pho:​RAF1|​pho:​_beta_-Arrestin2*@Early Endosomes map

In compartment: Golgi Apparatus

  1. Ca2+:​DAG:​RAF1|​pho:​RAS*|​pho:​RASGRP1@Golgi Apparatus map

In compartment: Late Endosomes

  1. GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map

  2. ERK*|​pho|​pho:​GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map

In compartment: Plasma Membrane

  1. GRB2:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane map

Participates in reactions:
As Reactant or Product:

  1. RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Cytoplasm map map RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Mitochondria map

  2. RAF1|​closed@Cytoplasm map + ATP@Cytoplasm map map RAF1|​S_pho|​closed@Cytoplasm map + ADP@Cytoplasm map
  3. RAF1|​S259_pho|​S621_pho|​S_pho|​closed@Cytoplasm map + YWHAB@Cytoplasm map map RAF1|​S259_pho|​S621_pho|​S_pho|​closed:​YWHAB@Cytoplasm map
  4. RAF1|​S259_pho|​S621_pho|​S_pho|​closed:​YWHAB@Cytoplasm map + GTP:​HRAS@Cytoplasm map map GTP:​HRAS:​RAF1|​S259_pho|​S621_pho|​S_pho|​closed@Cytoplasm map + YWHAB@Cytoplasm map
  5. GTP:​HRAS:​RAF1|​S259_pho|​S621_pho|​S_pho|​closed@Cytoplasm map + YWHAB@Cytoplasm map map GTP:​RAF1|​S259_pho|​S621_pho|​S_pho|​open:​YWHAB@Cytoplasm map
  6. GTP:​RAF1|​S259_pho|​S621_pho|​S_pho|​open:​YWHAB@Cytoplasm map + ATP@Cytoplasm map map RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​open@Cytoplasm map + ADP@Cytoplasm map
  7. RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​open@Cytoplasm map map RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​S338_pho|​active|​open@Cytoplasm map
  8. RAF1|​S_pho|​closed@Cytoplasm map + ATP@Cytoplasm map map RAF1|​S259_pho|​S621_pho|​S_pho|​closed@Cytoplasm map + ADP@Cytoplasm map
  9. RAF1@Cytoplasm map + GRB2:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane map map GRB2:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane map
  10. GRB2:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane map map GRB2:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane map + RAF1|​pho@Mitochondria map
  11. ERK*|​pho|​pho:​GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map map GRB2:​LAMTOR2:​MEK*:​MP1*:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map + ERK*@Cytoplasm map + RAF1@Cytoplasm map
  12. RAF1@Cytoplasm map + GRB2:​LAMTOR2:​MEK*:​MP1*:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map map GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map
  13. ERK*@Cytoplasm map + GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map map ERK*|​pho|​pho:​GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map
  14. RAF1@Cytoplasm map map RAF1|​pho@Cytoplasm map
  15. ERK*|​pho|​pho:​GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map map GRB2:​LAMTOR2:​MEK*|​pho|​pho:​MP1*:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Late Endosomes map + ERK*|​pho|​pho@Cytoplasm map
  16. RAF1@Cytoplasm map + Ca2+:​DAG:​RAS*|​pho:​RASGRP1@Golgi Apparatus map map Ca2+:​DAG:​RAF1|​pho:​RAS*|​pho:​RASGRP1@Golgi Apparatus map
  17. GPCR*|​pho:​GRK*:​_beta_-Arrestin2*@Plasma Membrane map + ERK*@Cytoplasm map + RAF1@Cytoplasm map + MEK*@Cytoplasm map map ERK*|​pho|​pho:​GPCR*:​GRK*:​MEK*|​pho|​pho:​RAF1|​pho:​_beta_-Arrestin2*@Early Endosomes map
  18. ERK*|​pho|​pho:​GPCR*:​GRK*:​MEK*|​pho|​pho:​RAF1|​pho:​_beta_-Arrestin2*@Early Endosomes map map GPCR*:​GRK*@Early Endosomes map + ERK*|​pho|​pho:​MEK*|​pho|​pho:​_beta_-Arrestin2*@Early Endosomes map + RAF1@Cytoplasm map

As Catalyser:

  1. BAD|​S91_unk:​BCL2@Mitochondrial outer membrane map map BCL2@Mitochondrial outer membrane map + BAD|​pho@Cytoplasm map

  2. BAD@Mitochondria map map BAD|​pho@Mitochondria map
  3. MEK1*@Cytoplasm map + ATP@Cytoplasm map map MEK1*|​S218_pho|​S222_pho|​active@Cytoplasm map + ADP@Cytoplasm map
  4. MEK2*@Cytoplasm map + ATP@Cytoplasm map map MEK2*|​S_pho|​active@Cytoplasm map + ADP@Cytoplasm map
  5. BAD@Mitochondria map map BAD|​pho@Cytoplasm map
  6. MEK*@Cytoplasm map map MEK*|​pho|​pho@Cytoplasm map
  7. ERK*:​MEK*:​SEF*@Golgi Apparatus map map ERK*|​pho|​pho:​MEK*|​pho|​pho:​SEF*@Cytoplasm map
  8. g_beta_-Catenin*@Nucleus map map r_beta_-Catenin*@Nucleus map

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