Reactome | MARK3 phosphorylates KSR1

MARK3 phosphorylates KSR1

Stable Identifier

R-HSA-5672948

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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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