Phosphorylation of RAF

Stable Identifier
Reaction [transition]
Homo sapiens
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Downstream of RAF dimerization and allosteric activation, RAF monomers and KSR1 undergo a series of activating phosphorylations in both the activation loop (AL) and, in the case of ARAF, RAF1 and KSR1, in the NtA . Phosphorylation of the activation loop residues (T491, S494 in RAF1, T452, T455 in ARAF and T599, S602 in BRAF) contributes to full kinase activity, although this may be less critical for ARAF, and RAFs in general, than for other kinases due to their regulation by 14-3-3 binding (Zhu et al, 2005; Zhang et al, 2000; Baljuls et al, 2008, reviewed in Matallanas et al, 2011; Udell et al, 2011). AL phosphorylation may occur through cis-autophosphorylation within the RAF dimer, although phosphorylation by other kinases is also possible (Hu et al, 2013; reviewed in Matallanas et al, 2011).

Phosphorylation in the RAF NtA region is required for full kinase activity, for interaction with MAP2K substrates and for the ability of activated RAF to act as an allosteric activator of other RAF monomers (Marais et al, 1995; Diaz et al, 1997; Xiang et al, 2002; Edin et al, 2005; Hu et al, 2013; Mason et al, 1999). Phosphorylation of these residues (S338 and Y441 in RAF1, S299 and Y302 in ARAF and Y602 in KSR1) may be mediated by a kinase of the SRC, JAK or PAK family kinases, by MAP2K kinases, calmodulin kinase CaMKII or through autophosphorylation by RAF itself (Marais et al, 1995; Xia et al, 1996; King et al, 1998; Sun et al, 2000; Tran et al, 2003; Tran et al, 2005; Salzano et al. 2012, Hu et al, 2013; reviewed in Matallanas et al, 2011). The phosphorylated NtA of RAF1 is also the binding site for the negative regulator PEPB1, also known as RKIP. PEBP1 binding to RAF1 prevents phosphorylation of the MAP2K substrates (Park et al, 2006; Rath et al, 2008; reviewed in Shin et al, 2009).

Literature References
PubMed ID Title Journal Year
12244094 Phosphorylation of 338SSYY341 regulates specific interaction between Raf-1 and MEK1

Wen, R, Waelde, CA, Luo, Z, Zang, M, Xiang, X

J. Biol. Chem. 2002
8876196 The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner

Griffin, JD, Rose, PE, Roberts, TM, Barber, DL, Xia, K, D'Andrea, AD, Inhorn, RC, Lee, RS, Mukhopadhyay, NK, Narsimhan, RP

Proc. Natl. Acad. Sci. U.S.A. 1996
15899852 Raf-1 serine 338 phosphorylation plays a key role in adhesion-dependent activation of extracellular signal-regulated kinase by epidermal growth factor

Juliano, RL, Edin, ML

Mol. Cell. Biol. 2005
15710605 B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms

Frost, JA, Wu, X, Tran, NH

J. Biol. Chem. 2005
12551923 Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition

Frost, JA, Tran, NH

J. Biol. Chem. 2003
9234708 Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling

MacDonald, S, Diaz, B, King, A, Filson, A, Marshall, M, Barnard, D

Mol. Cell. Biol. 1997
7542586 Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation

Marshall, CJ, Paterson, HF, Marais, R, Light, Y

EMBO J. 1995
11032810 Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601

Guan, KL, Zhang, BH

EMBO J. 2000
16093354 Identification of Raf-1 S471 as a novel phosphorylation site critical for Raf-1 and B-Raf kinase activities and for MEK binding

Zhu, J, Bronisz, A, Luo, Z, Sun, H, Balan, K, Avruch, J, Balan, V, Tzivion, G, Leicht, DT, Qin, J

Mol. Biol. Cell 2005
10712905 Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak

Marshall, MS, King, AJ, Sun, H, Diaz, HB

Curr. Biol. 2000
9823899 The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338

Marshall, MS, King, AJ, Diaz, B, Barnard, D, Sun, H, Bagrodia, S, Miao, W

Nature 1998
17097642 Regulation of RKIP binding to the N-region of the Raf-1 kinase

Yeung, KC, Beach, S, Park, S, Luo, Z, Kelly, SM, Kolch, W, Xiang, X, Rath, O

FEBS Lett. 2006
20820846 Mechanistic principles of RAF kinase signaling

Sicheri, F, Udell, CM, Rajakulendran, T, Therrien, M

Cell. Mol. Life Sci. 2011
22592532 Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation

Vitale, M, Bifulco, M, Postiglione, L, Salzano, M, Russo, E, Rusciano, MR

Cell Cycle 2012
18294816 The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK

Yeung, KC, Banfield, MJ, Brady, RL, Dignam, JD, Sedivy, JM, Lee, YC, Park, S, Tang, HH, Kolch, W, Rath, O

Cell. Signal. 2008
10205168 Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation

Springer, CJ, Superti-Furga, G, Cooper, RG, Mason, CS, Marshall, CJ, Marais, R

EMBO J. 1999
23993095 Allosteric activation of functionally asymmetric RAF kinase dimers

Stites, EC, Taylor, SS, Yu, H, Hu, J, Germino, EA, Meharena, HS, Stork, PJ, Kornev, AP, Shaw, AS

Cell 2013
19158341 Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway

Fee, F, Shin, SY, McFerran, B, Cho, KH, Kolch, W, Choo, SM, Rath, O

J. Cell. Sci. 2009
9020159 Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases

Paterson, HF, Light, Y, Mason, CS, Marshall, CJ, Marais, R

J. Biol. Chem. 1997
21779496 Raf family kinases: old dogs have learned new tricks

Romano, D, Matallanas, D, Rauch, J, Zebisch, A, Birtwistle, M, Kolch, W, von Kriegsheim, A

Genes Cancer 2011
18662992 Positive regulation of A-RAF by phosphorylation of isoform-specific hinge segment and identification of novel phosphorylation sites

Baljuls, A, Mueller, T, Hekman, M, Zahedi, RP, Sickmann, A, Rapp, UR, Schmitz, W

J. Biol. Chem. 2008
Catalyst Activity

protein serine/threonine/tyrosine kinase activity of RAF activating kinases [plasma membrane]

Orthologous Events
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