Regardless of the level of E cadherin an increase

Regardless of the level of E-cadherin, an increase of N-cadherin in epithelial cancer 85 8 sale is sufficient to induce an invasive phenotype as we have reviewed in the earlier sections. When collagen activates integrin α2β1 and DDR1, a signal to upregulate N-cadherin will be initiated by each receptor (Fig. 3) [11]. Integrin α2β1 activates FAK, while DDR1 induces the activity of effector proline-rich tyrosine kinase 2 (Pyk2), which belongs to the same family as FAK. Phosphorylation of Y513 on DDR1b is critical for the activation of Pyk2 [12]. Once Y513 of DDR1b is phosphorylated, it will function as a docking site for the PTB domain of the adaptor protein Shc1, which is required for the interaction between DDR1 and Pyk2. Knocking-down Shc1 can diminish the upregulation of N-cadherin induced by collagen. When FAK and Pyk2 are activated, the two signaling cascades will merge to a downstream scaffold protein called p130 Crk-associated substrate (p130CAS). Many studies have reported that FAK and Pyk2 can interact with p130CAS, and these interactions are important for cell and tissue processes, including angiogenesis of pulmonary vascular endothelial cells and the formation of the sealing zone during osteoclast activation [61,92]. FAK and Pyk2 interact with the Src homology 3 (SH3) domain of p130CAS [93]. However, whether these proteins interact during cadherin switching in a similar way is largely unknown. In addition, we have found that pseudopodium-enriched atypical kinase 1 (PEAK1) is involved in DDR1 signaling [94]. PEAK1 is a cytoskeleton-associated kinase previously reported to regulate p130CAS-Crk-paxillin after Src-induced tyrosine phosphorylation [95]. Moreover, Src is also required for the priming activation of FAK and Pyk2 [75,96]. Therefore, we suggest that a Src-FAK/Pyk2-p130CAS-PEAK1 interacting network may exist in mediating collagen induction of N-cadherin expression and morphological changes. It is worth mentioning that although integrin α2β1 can initiate signaling through FAK, it is not always required for collagen-induced cadherin switching [12]. For example, in BxPC3, α2β1 integrin and DDR1 signaling seem to cooperate and contribute similarly to cadherin switching; however, in L3.6pl pancreatic cancer cells, collagen-induced cadherin switching is mediated by DDR1-Pyk2 and not integrins [12]. The activation of p130CAS results in a Rap1-MLK3-MKK7-JNK1-cJun signaling cascade. Rap1 is a small GTPase that activates the JNK signaling pathway [97]. In pancreatic cancer, expression of Rap1GAP, a negative regulator of Rap1 activation, is significantly downregulated [98]. The loss of Rap1GAP expression occurs in 60% of invasive pancreatic cancers. This strongly suggests that the Rap1 signaling cascade is involved in the progression of cancer and cadherin switching is potentially a Rap1-mediated event. The signaling cascade activates c-Jun, which in combination with c-Fos, forms the AP-1 early response transcription factor [99]. Although whether N-cadherin is directly regulated by c-Jun is unknown, it has been shown that c-Jun can drive EMT by upregulating Slug [100]. Thus, it is probable that EMT transcription factors are involved in collagen-induced cadherin switching.