Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1.
Tumor cells undergo epithelial-to-mesenchymal transition (EMT) to convert from a benign to a malignant phenotype. Our recent focus has been signaling pathways that promote EMT in response to collagen. We have shown that human pancreatic cancer cells respond to collagen by up-regulating N-cadherin, which promotes tumor growth, invasion, and metastasis. Initial characterization showed that knocking down c-Jun NH2-terminal kinase prevented N-cadherin up-regulation and limited tumor growth and invasion in a mouse model for pancreatic cancer. The current study was designed to understand the pathway from collagen to N-cadherin up-regulation. Initiation of the signal requires two collagen receptors, alpha2beta1 integrin and discoidin domain receptor (DDR) 1. Each receptor propagates signals through separate pathways that converge to up-regulate N-cadherin. Focal adhesion kinase (FAK)-related protein tyrosine kinase (Pyk2) is downstream of DDR1, whereas FAK is downstream of alpha2beta1 integrin. Both receptor complexes rely on the p130 Crk-associated substrate scaffold. Interestingly, Rap1, but not Rho family guanosine triphosphatases, is required for the response to collagen I.
Shintani
Yasushi
Y
Department of Oral Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Fukumoto
Yuri
Y
Chaika
Nina
N
Svoboda
Robert
R
Wheelock
Margaret J
MJ
Johnson
Keith R
KR
D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
C493841:BCAR1 protein, human; D015820:Cadherins; D024042:Collagen Type I; D050719:Crk-Associated Substrate Protein; D038982:Integrin alpha2beta1; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020827:rap1 GTP-Binding Proteins