Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

Abstract

Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPAinduced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation-specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo.

Reciprocal regulation of PKA and Rac signaling

“…Fourth, we have revealed that in the ovarian cancer cell line OVCAR3, the proliferation-relevant βAR-PKA signaling axis (24,47) is linked to Rac-PAK-Erk1/2-mediated activation of the transcription factor Elk1. Overall our findings disclose a unique crossroad of frequently targeted receptor cascades (RTK, βAR) that integrates cAMP responses and GTPase activities spatially and temporally, leading to modulation of the crucial Raf-Mek-Erk signaling axis (11)(12)(13)(14)(15)(16). It has been described that PKA activities regulate GEFs and GAPs that change the GTP loading of Rac1, resulting in changes of signaling related to morphological alterations of the cytoskeleton (48)(49)(50).…”

“…1G, 2F, and 3 A and B). Next, in two independent cell systems, we tested whether PKA activation causes PAK phosphorylation, which has been described to modulate RafMek-Erk signaling (16,(34)(35)(36): First, we show that both overexpression of PKAc and Forskolin treatment elevates PAK1-Thr423 and PAK2-Thr402 phosphorylation (Fig. S4A).…”

“…It has been reported that Rac1 participates to promote the Raf-MekErk cascade (16,(34)(35)(36). To investigate the role of GTP-Rac1 in Erk1/2 activation, we used HEK293 cells, which show no increase of Erk1/2 phosphorylation in response to Forskolin alone (18).…”

“…Such fundamental cellular functions are controlled by mitogenic signals that are transmitted through cascades involving crucially regulated mitogen-activated protein kinases (MAPK) like Erk1/2 (14). It has been described that the Rho GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) participates in the regulation of transformation, growth, and survival of tumor cells at least partially by controlling extracellular signal-regulated kinase (Erk)1/2 activation (15,16). So far, several functionally diverse means have been illustrated how hormone-triggered cAMP pulses participate in the regulation and transmission of mitogenic signals originating from RTK via the Raf-Mek-Erk pathway (11)(12)(13).…”

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

“…Similarly, we found that Wnt protein is able to induce PAK1 activation in HEK293T cells and endogenous PAK1 activity is partially required for full b-catenin accumulation in both HEK293T and mouse L-cells upon Wnt stimulation. In colon cancer cells, signaling from K-Ras/Rac1 (Lee et al, 2007;Wang et al, 2010b), IGF (Sun et al, 2009) or EGF (Galisteo et al, 1996;Lu et al, 1997) pathways all may induce PAK1 activation, which maintains the high phosphorylation state of b-catenin S675.…”