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Gene Review

KSR1  -  kinase suppressor of ras 1

Homo sapiens

Synonyms: KSR, Kinase suppressor of Ras 1, RSU2
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Disease relevance of KSR1


High impact information on KSR1


Biological context of KSR1

  • Here we describe details of the methods, including RNA interference, ubiquitin ligase assays, and protein complex analysis, that can be used to display the Ras-sensitive contribution of IMP to KSR-dependent modulation of the Raf/MEK/ERK pathway [8].
  • Cdc25C-associated kinase 1 (C-TAK1) has been implicated in cell cycle regulation and Ras signaling through its interactions with two putative substrates, the Cdc25C phosphatase and the MAPK scaffold KSR1 [9].
  • These data demonstrate that phosphorylation and stability of the molecular scaffold KSR1 are critical regulators of growth factor-specific responses that promote cell proliferation [10].
  • Phosphorylation regulates KSR1 stability, ERK activation, and cell proliferation [10].
  • Nuclear import of KSR was blocked by mutations that inhibit the interaction of KSR with MEK [11].

Anatomical context of KSR1

  • Using this assay, we show that KSR immunoprecipitated from quiescent COS-7 cells overexpressing Flag-tagged KSR was inactive, but its activity was rapidly and markedly induced upon epidermal growth factor treatment [12].
  • KSR1(-/-) mouse embryo fibroblasts expressing KSR1.TVSA proliferate two times faster and grow to a higher density than cells expressing the same level of wild-type KSR1 [10].
  • Michaelis constants, maximum velocities, estradiol-17beta/testosterone (E(2)/T) activity ratios and inhibition patterns were consistent with a predominance of microsomal 17HSD/KSR2 and cytosolic 17HSD/KSR5, isoforms reactive with both E(2) and T, with evidence of estrogenic 17HSD/KSR1 in cytosol from some samples [13].
  • Coimmunoprecipitation experiments demonstrated that KSR-1 bound to beta1 gamma3 subunits when all three were transfected into cultured cells [4].
  • RESULTS: We examined the physiological role of KSR in vertebrate signal transduction using Xenopus laevis oocytes [14].

Associations of KSR1 with chemical compounds

  • Binding of the CK2 holoenzyme is constitutive and requires the basic surface region of the KSR1 atypical C1 domain [15].
  • Ras-Sensitive IMP Modulation of the Raf/MEK/ERK Cascade Through KSR1 [8].
  • In agreement with KSR1 degradation data, high-Nm23-H1-expression cells were preferentially inhibited in anchorage-independent colonization assays by 17-AAG [16].
  • KSR accumulated in the nucleus within 2 h of treatment with leptomycin B, suggesting that KSR cycles continuously through the nucleus [11].
  • Here we demonstrate that the connector enhancer of Ksr1, CNK1, mediates Src-dependent tyrosine phosphorylation and activation of Raf-1 [17].

Physical interactions of KSR1

  • These findings identify CK2 as a novel component of the KSR1 scaffolding complex that facilitates ERK cascade signaling by functioning as a Raf family N-Region kinase [15].
  • KSR interacts constitutively with MEK and translocates from the cytosol to the plasma membrane on Ras activation [18].

Other interactions of KSR1

  • Moreover, we find that the KSR1/CK2 interaction is required for KSR1 to maximally facilitate ERK cascade signaling and contributes to the regulation of Raf kinase activity [15].
  • Furthermore, endogenous KSR isolated from A431 cells, which contain high levels of activated EGF receptor, displays constitutively enhanced kinase activity [12].
  • The recognition of EGF as a potent activator of KSR kinase activity and the availability of a well defined in vitro kinase assay should facilitate the definition of the function of KSR as a Ras-effector molecule [12].
  • Cells expressing high levels of Nm23-H1 exhibited increased KSR1 degradation in the presence of either cycloheximide or an Hsp90-directed drug currently in clinical trial, 17-allylamino-17-demethoxygeldanamycin (17-AAG) [16].
  • Increased coimmunoprecipitation of Hsp90 with KSR1 was observed in either stable or transient transfectants of nm23-H1 in MDA-MB-435 human breast carcinoma cells [16].

Analytical, diagnostic and therapeutic context of KSR1


  1. Inflammatory bowel disease reveals the kinase activity of KSR1. Kolesnick, R., Xing, H.R. J. Clin. Invest. (2004) [Pubmed]
  2. Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer. Xing, H.R., Cordon-Cardo, C., Deng, X., Tong, W., Campodonico, L., Fuks, Z., Kolesnick, R. Nat. Med. (2003) [Pubmed]
  3. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Lozano, J., Xing, R., Cai, Z., Jensen, H.L., Trempus, C., Mark, W., Cannon, R., Kolesnick, R. Cancer Res. (2003) [Pubmed]
  4. KSR-1 binds to G-protein betagamma subunits and inhibits beta gamma-induced mitogen-activated protein kinase activation. Bell, B., Xing, H., Yan, K., Gautam, N., Muslin, A.J. J. Biol. Chem. (1999) [Pubmed]
  5. Male pseudohermaphroditism due to testicular 17-ketosteroid reductase deficiency. Schaison, G., Sitruk, L.R. Horm. Metab. Res. (1976) [Pubmed]
  6. C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Müller, J., Ory, S., Copeland, T., Piwnica-Worms, H., Morrison, D.K. Mol. Cell (2001) [Pubmed]
  7. The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12-induced and replicative senescence. Kortum, R.L., Johnson, H.J., Costanzo, D.L., Volle, D.J., Razidlo, G.L., Fusello, A.M., Shaw, A.S., Lewis, R.E. Mol. Cell. Biol. (2006) [Pubmed]
  8. Ras-Sensitive IMP Modulation of the Raf/MEK/ERK Cascade Through KSR1. Matheny, S.A., White, M.A. Meth. Enzymol. (2005) [Pubmed]
  9. Functional analysis of C-TAK1 substrate binding and identification of PKP2 as a new C-TAK1 substrate. Müller, J., Ritt, D.A., Copeland, T.D., Morrison, D.K. EMBO J. (2003) [Pubmed]
  10. Phosphorylation regulates KSR1 stability, ERK activation, and cell proliferation. Razidlo, G.L., Kortum, R.L., Haferbier, J.L., Lewis, R.E. J. Biol. Chem. (2004) [Pubmed]
  11. Phosphorylation regulates the nucleocytoplasmic distribution of kinase suppressor of Ras. Brennan, J.A., Volle, D.J., Chaika, O.V., Lewis, R.E. J. Biol. Chem. (2002) [Pubmed]
  12. Epidermal growth factor treatment enhances the kinase activity of kinase suppressor of Ras. Xing, H.R., Lozano, J., Kolesnick, R. J. Biol. Chem. (2000) [Pubmed]
  13. Androgenic and estrogenic 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase in human ovarian epithelial tumors: evidence for the type 1, 2 and 5 isoforms. Blomquist, C.H., Bonenfant, M., McGinley, D.M., Posalaky, Z., Lakatua, D.J., Tuli-Puri, S., Bealka, D.G., Tremblay, Y. J. Steroid Biochem. Mol. Biol. (2002) [Pubmed]
  14. The protein kinase KSR interacts with 14-3-3 protein and Raf. Xing, H., Kornfeld, K., Muslin, A.J. Curr. Biol. (1997) [Pubmed]
  15. CK2 Is a Component of the KSR1 Scaffold Complex that Contributes to Raf Kinase Activation. Ritt, D.A., Zhou, M., Conrads, T.P., Veenstra, T.D., Copeland, T.D., Morrison, D.K. Curr. Biol. (2007) [Pubmed]
  16. Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Salerno, M., Palmieri, D., Bouadis, A., Halverson, D., Steeg, P.S. Mol. Cell. Biol. (2005) [Pubmed]
  17. CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. Ziogas, A., Moelling, K., Radziwill, G. J. Biol. Chem. (2005) [Pubmed]
  18. KSR Regulation of the Raf-MEK-ERK Cascade. Ritt, D.A., Daar, I.O., Morrison, D.K. Meth. Enzymol. (2005) [Pubmed]
  19. Human leptospirosis in Erode, South India: serology, isolation, and characterization of the isolates by randomly amplified polymorphic DNA (RAPD) fingerprinting. Natarajaseenivasan, K., Prabhu, N., Selvanayaki, K., Raja, S.S., Ratnam, S. Jpn. J. Infect. Dis. (2004) [Pubmed]
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