ADAM10 and 17 cleave their type I transmembrane substrate proteins at 715 residues from the plasma membrane (Supplemental Table S1; Caescuetal., 2009). DDR1 mutant, we found that ADAM10-dependent DDR1 shedding regulates the half-life of collagen-induced phosphorylation of the receptor. Our data also revealed that ADAM10 plays an important role in regulating DDR1-mediated NBI-98782 cell adhesion to achieve efficient cell migration on collagen matrices. == INTRODUCTION == Extracellular matrix (ECM) is essential in multicellular organisms to maintain functional tissue structures; it acts as scaffolding to support cell migration and as a reservoir for growth factors. In NBI-98782 addition , components of ECM can directly transmit signals to cells supporting cell survival and differentiation. Among them, the most abundant ECM component in mammals is collagen, and there are at least five different types of collagen receptors in humans, which include integrins, discoidin domain receptors (DDRs), glycoprotein VI, leukocyte-associated, immunoglobulin-like receptors, and mannose receptors such as Endo180. Among them, DDRs are unique, as they belong to the receptor tyrosine kinase (RTK) family (Leitinger and Hohenester, 2007; Leitinger, 2011). There are two receptors in this RTK subfamily, DDR1 and DDR2; DDR1 is expressed in epithelial cells primarily, whereas DDR2 is found in mesenchymal cells NBI-98782 (Vogel, 1999; Leitinger, 2011). They share 50% sequence homology, and the common domain structure of DDRs includes a discoidin-homology domain (DD), a discoidin-like domain (DLD), an extracellular juxtamembrane domain, a transmembrane domain, a cytosolic juxtamembrane domain, and a tyrosine kinase domain (TKD). Collagen binding to the DD induces receptor autophosphorylation (Shrivastavaet al., 1997; Vogelet al., 1997; Leitinger, 2003), and it has been also shown that Src is involved in DDR1-dependent collagen signaling (Luet al., 2011). Activation of DDR1 and DDR2 can be induced by different collagens, including type I, II, III, and V collagens, and DDR1 can also be stimulated by type IV collagen (Shrivastavaet al., 1997; Vogelet al., 1997). DDRs are believed to play important roles during development, as both DDR1- and DDR2-null mice showed dwarfism, and DDR1-null mice also showed abnormal development of epithelial organs (Labradoret al., 2001; Vogelet al., 2001). DDRs are also implicated in disease development, including fibrotic disorders of several organs and various cancers (Vogelet al., 2006; Leitinger, 2014). It has been reported NBI-98782 that collagen signals mediated by both DDR1 and 21 integrin up-regulate N-cadherin NBI-98782 expression, which promotes epithelialmesenchymal transition (Shintaniet al., 2008). It has also been reported that DDR1 is an essential transmitter of microenvironmental signals for cell survival, homing, and colonization of lung cancer to promote bone metastasis (Valenciaet al., 2012). DDR2 has been implicated in the development of osteoarthritis, as it was shown to be up-regulated in chondrocytes in osteoarthritic cartilage (Xuet al., 2007), and DDR2 activation was shown to induce expression of matrix metalloproteinase 13, which degrades cartilage collagen in osteoarthritis (Xuet al., 2007). Signaling driven by RTKs must be tightly regulated, since uncontrolled RTK activities would result in tumorigenesis (Porter and Vaillancourt, 1998). To maintain the proper level of RTK signaling in a temporal and spatial manner, at least the following three mechanisms are in place (Blobel, 2005; Dreuxet al., 2006; Lemmon and Schlessinger, 2010). First, RTK activation is dependent on its ligand bioavailability. For many RTKs, their ligands are soluble factors and are not present or bioavailable under normal conditions. Expression of the ligands can be induced or the ligands become bioavailable to the RTKs upon different stimuli (Sunnarborget al., 2002). Thus this regulation of ligand availability for different RTKs is an effective mechanism to control RTK signaling. A second regulation can be endocytosis of the ligandRTK complex from the cell surface (Marmor and Yarden, 2004; Reiss and Saftig, 2009; Weber and Saftig, 2012; Goh and Sorkin, 2013). This effectively terminates signaling by removing receptors from the cell surface and dissociates ligands from the RTK Plscr4 in endocytic vesicles, followed by intracellular degradation of ligand or receptor molecules or both (Marmor and Yarden, 2004; Goh and Sorkin, 2013). Third, ectodomain shedding of different receptors, including RTKs, can regulate their signaling. This receptor shedding controls the levels of receptor on the cell.