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  • Several studies on the collagen receptor DDR

    2021-06-11

    Several studies on the collagen receptor DDR1 have revealed a defined collagen signaling pathway that causes cell scattering and cadherin switching. As mentioned earlier, DDR hematopoietic stem cells on collagens are distinct from integrin binding sites; therefore, the same collagen protein can bind to DDR and integrin receptors at the same time, leading to the simultaneous activation of each receptor. In the pancreatic cancer cell line BxPC3, upregulation of N-cadherin is mediated by integrin α2β1 and DDR1 [11]. As a result, the expression of the inappropriate N-cadherin disrupted E-cadherin-mediated cell-cell adhesion and resulted in a scattering cell phenotype [87]. Interestingly, while the upregulation of N-cadherin is often consistent among different cancer cell lines, the change of the expression of E-cadherin is more cell line dependent. The disruption of E-cadherin might be caused by the activation and recruitment of FAK and Src to the E-cadherin complex [88,89]. For example, in colon cancer, FAK phosphorylates Src in an integrin-dependent manner, resulting in the disorganization of E-cadherin-associated intercellular contacts [90]. Moreover, inhibition of FAK or Src activity prevents E-cadherin endocytosis and TGFβ-induced downregulation of E-cadherin [91]. This suggests that unlike N-cadherin, the downregulation of E-cadherin during collagen-induced cadherin switching may be mediated by integrin receptors instead of DDR1, since the knockdown of DDR1 in many pancreatic cancer cell lines does not affect the expression of E-cadherin [12]. Regardless of the level of E-cadherin, an increase of N-cadherin in epithelial cancer cells 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.