Activated mutant NRasQ61K drives aberrant melanocyte signaling, survival, and invasiveness via a rac1-Dependent mechanism

Li, A., Ma, Y., Jin, M., Mason, S., Mort, R.L., Blyth, K. , Larue, L., Sansom, O.J. and Machesky, L.M. (2012) Activated mutant NRasQ61K drives aberrant melanocyte signaling, survival, and invasiveness via a rac1-Dependent mechanism. Journal of Investigative Dermatology, 132(11), pp. 2610-2621. (doi: 10.1038/jid.2012.186)

Abstract

Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal–regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRasQ61K on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRasQ61K in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRasQ61K does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRasQ61K induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blyth, Professor Karen and Jin, Ms Meng and Li, Mr Ang and Machesky, Professor Laura and Ma, Dr Yafeng and Mason, Miss Susan and Sansom, Professor Owen
• Authors: Li, A., Ma, Y., Jin, M., Mason, S., Mort, R.L., Blyth, K., Larue, L., Sansom, O.J., and Machesky, L.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Investigative Dermatology
• Publisher: Nature Publishing Group
• ISSN: 0022-202X
• Published Online: 21 June 2012
• Copyright Holders: Copyright © 2012 The Society for Investigative Dermatology
• First Published: First published in Journal of Investigative Dermatology 132(11):2610-2621
• Publisher Policy: Reproduced under a Creative Commons License