MARK3 phosphorylates KSR1

Stable Identifier
Reaction [transition]
Homo sapiens
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KSR1 (Kinase suppressor of RAS 1) was originally identified in Drosophila and C. elegans as a suppressor of activated RAS, and is one of a number of scaffolding proteins that bring RAS-RAF-MAPK members together to promote pathway activation (Therrien et al, 1995; Kornfeld et al, 1995; Sundaram et al, 1995; reviewed in Zhang et al, 2013). Consistent with its role as a scaffolding protein, KSR1 interacts with all of the kinases of the MAPK pathway. Interaction with the MEK proteins MAP2K1 and MAP2K2 is constitutive, while pathway activation promotes heterodimerization with activated RAF proteins and subsequent interaction with ERK/MAPK proteins (Rajakulendran et al, 2009; Therrien et al, 1996; McKay et al, 2009; Hu et al, 2011; Hu et al, 2013; Brennan et al, 2011; note, however, that for simplicity MAP2K/MEK proteins are not depicted as part of this reaction).
Like the RAF proteins, KSR1 is maintained in an inactive state in quiescent cells by interaction with 14-3-3 dimers; this interaction is promoted by phosphorylation of KSR1 residues S311 and S406 by the MAP/microtubule affinity-regulating kinase 3 (MARK3), which is constitutively bound to KSR1 (Muller et al, 2001).

Literature References
PubMed ID Title Journal Year
8946910 KSR modulates signal propagation within the MAPK cascade

Rubin, GM, Morrison, DK, Michaud, NR, Therrien, M

Genes Dev. 1996
23863182 The dual function of KSR1: a pseudokinase and beyond

Koo, CY, Stebbing, J, Giamas, G, Zhang, H

Biochem. Soc. Trans. 2013
8521512 KSR, a novel protein kinase required for RAS signal transduction

Karim, FD, Solomon, NM, Chang, HC, Wassarman, DA, Rubin, GM, Therrien, M

Cell 1995
11741534 C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1

Piwnica-Worms, H, Muller, J, Ory, S, Copeland, T, Morrison, DK

Mol Cell 2001
19541618 Signaling dynamics of the KSR1 scaffold complex

McKay, MM, Ritt, DA, Morrison, DK

Proc. Natl. Acad. Sci. U.S.A. 2009
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
21441910 A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK

Shokat, KM, Brennan, DF, Hertz, NT, Chao, WC, Burlingame, AL, Barford, D, Dar, AC

Nature 2011
19727074 A dimerization-dependent mechanism drives RAF catalytic activation

Sicheri, F, Sahmi, M, Rajakulendran, T, Lefrancois, M, Therrien, M

Nature 2009
21441104 Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF

Taylor, SS, Yu, H, Hu, J, Kornev, AP, Shaw, AS, Filbert, EL, Zhao, J

Proc. Natl. Acad. Sci. U.S.A. 2011
8521513 The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction

Han, M, Sundaram, M

Cell 1995
8521514 The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans

Kornfeld, K, Horvitz, HR, Hom, DB

Cell 1995
Catalyst Activity

protein serine/threonine kinase activity of KSR1:MARK3 [cytosol]

Orthologous Events
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