Integrin α3β1 plays a crucial role in tumor formation in the two-stage chemical carcinogenesis model (DMBA and TPA treatment). However, the mechanisms whereby the expression of α3β1 influences key oncogenic drivers of this established model are not known yet. Using an in vivo mouse model with epidermal deletion of α3β1 and in vitro Matrigel cultures of transformed keratinocytes, we demonstrate the central role of α3β1 in promoting the activation of several protumorigenic signaling pathways during the initiation of DMBA/TPA‒driven tumorigenesis. In transformed keratinocytes, α3β1-mediated focal adhesion kinase/Src activation leads to in vitro growth of spheroids and to strong Akt and STAT 3 activation when the α3β1-binding partner tetraspanin CD151 is present to stabilize cell‒cell adhesion and promote Smad2 phosphorylation. Remarkably, α3β1 and CD151 can support Akt and STAT 3 activity independently of α3β1 ligation by laminin-332 and as such control the essential survival signals required for suprabasal keratin-10 expression during keratinocyte differentiation. These data demonstrate that α3β1 together with CD151 regulate the signaling pathways that control the survival of differentiating keratinocytes and provide a mechanistic understanding of the essential role of α3β1 in early stages of skin cancer development.