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Gene Review

CNKSR1  -  connector enhancer of kinase suppressor of...

Homo sapiens

Synonyms: CNK, CNK homolog protein 1, CNK1, Connector enhancer of KSR 1, Connector enhancer of KSR-like, ...
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Disease relevance of CNKSR1

  • Immunoprecipitates of MST1 endogenous to LoVo colon cancer cells contain endogenous CNK1; however, no association of these two polypeptides can be detected in a yeast two-hybrid assay [1].

High impact information on CNKSR1

  • KSR overexpression constitutively activates Raf-1 [2].
  • Kinase suppressor of Ras (KSR) is a conserved component of the Ras pathway that interacts directly with MEK and MAPK [3].
  • Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways [4].
  • Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho [5].
  • Down-regulation of endogenously expressed CNK1 by small inhibitory RNA interferes with Src-dependent activation of ERK [6].

Biological context of CNKSR1


Anatomical context of CNKSR1

  • Overexpression of hCNK1 does not affect the actin cytoskeleton and does not modify the appearance of stress fibers in cells overexpressing a constitutively active form of RhoA [8].
  • Microarray and quantitative polymerase chain reaction-based gene expression profiling demonstrates that definitive endoderm formation under these conditions closely parallels that following specification with elevated Activin A and low fetal calf serum (FCS)/knockout serum replacement (KSR) [9].

Associations of CNKSR1 with chemical compounds


Physical interactions of CNKSR1


Regulatory relationships of CNKSR1

  • CNK1 regulates the activation of Raf-1 by Src in a concentration-dependent manner typical for a scaffold protein [6].

Other interactions of CNKSR1

  • In contrast, hCNK1 was able to significantly decrease the RhoA-induced transcriptional activity of the serum response element (SRE) without effect on the Ras-induced SRE activation [8].
  • Thus, CNK1 allows cross-talk between Src and Raf-1 and is essential for the full activation of Raf-1 [6].

Analytical, diagnostic and therapeutic context of CNKSR1


  1. The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. Rabizadeh, S., Xavier, R.J., Ishiguro, K., Bernabeortiz, J., Lopez-Ilasaca, M., Khokhlatchev, A., Mollahan, P., Pfeifer, G.P., Avruch, J., Seed, B. J. Biol. Chem. (2004) [Pubmed]
  2. Kinase suppressor of Ras is ceramide-activated protein kinase. Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X.H., Basu, S., McGinley, M., Chan-Hui, P.Y., Lichenstein, H., Kolesnick, R. Cell (1997) [Pubmed]
  3. 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]
  4. Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Jaffe, A.B., Aspenström, P., Hall, A. Mol. Cell. Biol. (2004) [Pubmed]
  5. Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho. Jaffe, A.B., Hall, A., Schmidt, A. Curr. Biol. (2005) [Pubmed]
  6. CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. Ziogas, A., Moelling, K., Radziwill, G. J. Biol. Chem. (2005) [Pubmed]
  7. Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. Hartsough, M.T., Morrison, D.K., Salerno, M., Palmieri, D., Ouatas, T., Mair, M., Patrick, J., Steeg, P.S. J. Biol. Chem. (2002) [Pubmed]
  8. Bioluminescence resonance energy transfer identify scaffold protein CNK1 interactions in intact cells. Lopez-Ilasaca, M.A., Bernabe-Ortiz, J.C., Na, S.Y., Dzau, V.J., Xavier, R.J. FEBS Lett. (2005) [Pubmed]
  9. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. McLean, A.B., D'Amour, K.A., Jones, K.L., Krishnamoorthy, M., Kulik, M.J., Reynolds, D.M., Sheppard, A.M., Liu, H., Xu, Y., Baetge, E.E., Dalton, S. Stem Cells (2007) [Pubmed]
  10. Kinase suppressor of Ras signals through Thr269 of c-Raf-1. Xing, H.R., Kolesnick, R. J. Biol. Chem. (2001) [Pubmed]
  11. The scaffold protein CNK1 interacts with the angiotensin II type 2 receptor. Fritz, R.D., Radziwill, G. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
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