Directing Rho Signals

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Science's STKE  15 Mar 2005:
Vol. 2005, Issue 275, pp. tw102
DOI: 10.1126/stke.2752005tw102

Guanosine triphosphatases (GTPases) in the Rho family are involved in regulating such cellular processes as cytoskeletal organization, gene transcription, cell cycle progression, and malignant transformation. These small GTPases can be activated by multiple guanine nucleotide exchange factors (GEFs) and have numerous targets. Jaffe et al., who previously determined that the Rho target CNK1 interacts with a second Rho target protein, investigated the possibility that it acts as a scaffolding protein to direct Rho signaling into a particular pathway. When FLAG-tagged Rho was coexpressed in HeLa cells with myc-tagged Rho-GEFs, it could be coimmunoprecipitated with either of two Rho-GEFs, Net1 or p115RhoGEF (but not with a third). CNK1 inhibited the ability of p155RhoGEF or an activated form of Net1 (Net1ΔN) to activate SRF (serum response factor) and induce stress fiber formation, whereas it enhanced p155RhoGEF- or Net1ΔN-dependent phosphorylation of c-Jun N-terminal kinase (JNK) and of c-Jun. When coexpressed in HeLa cells, CNK1 coimmunoprecipitated with several members of the JNK mitogen-associated protein kinase (JNK MAPK) cascade, including MLK2 and MLK3 (both MAPK kinase kinases), and MKK7 (a MAPK kinase), but not with MKK4 (another JNK pathway MAPK kinase). CNK also enabled p115RhoGEF to coimmunoprecipitate with MKK7. A HeLa cell line in which endogenous CNK1 was depleted showed attenuated c-Jun phosphorylation when transfected with constitutively active Rho or p115RhoGEF, with no reduction in stress fiber formation. Moreover, activation of the JNK MAPK pathway through stimulation of Gα12/13 (which activates p115RhoGEF) depended on endogenous CNK1. Thus, CNK1 appears to play a role in determining Rho signaling specificity by promoting Rho activation of the JNK MAPK pathway.

A. B. Jaffe, A. Hall, A. Schmidt, Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho. Curr. Biol. 15, 405-412 (2005). [PubMed]

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