Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism.
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 NRas(Q61K) 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 NRas(Q61K) in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRas(Q61K) does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRas(Q61K) 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.
The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK.
Ang
A
Li
Yafeng
Y
Ma
Meng
M
Jin
Susan
S
Mason
Richard L
RL
Mort
Karen
K
Blyth
Lionel
L
Larue
Owen J
OJ
Sansom
Laura M
LM
Machesky
D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D020405:Dermis / Q000166:cytology / Q000196:embryology; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology; D005260:Female; D006200:Hair Color / Q000235:genetics; D017495:Hyperpigmentation / Q000235:genetics; D008207:Lymphatic Metastasis / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008544:Melanocytes / Q000166:cytology / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009368:Neoplasm Transplantation; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000378:metabolism; D009924:Organ Culture Techniques; D011247:Pregnancy; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D015689:Oncogene Protein p21(ras); D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein