Whichever interactions are formed between the DS domains and

Whichever interactions are formed between the DS domains and the collagen ligand, they are expected to lead to structural changes within the DDR dimer that are propagated across the cell membrane to result in DDR autophosphorylation (Noordeen et al., 2006). Tight coupling of the extracellular conformational changes to intracellular domain arrangements is difficult to imagine in the DDRs, given their long, and presumably flexible, JM regions. Recent studies of the epidermal growth factor receptor (EGFR) have shown that the conformational coupling across the cell membrane is looser than commonly believed, even in a receptor with less extensive JM regions (Lu et al., 2010, Mi et al., 2011). However, one important difference is that the TM helices of DDRs have a much higher propensity for self-interactions than that of EGFR (Finger et al., 2009). We propose that the TM helices are largely responsible for constitutive DDR dimerization (Noordeen et al., 2006), but that collagen-induced interactions involving the DS domains are additionally required for DDR activation.
Experimental Procedures
Acknowledgments
Dendritic Picroside II mg (DCs) are the most central player in the initiation and direction of immune responses as effective antigen-presenting cells (APCs). In general, DCs have been found in the immature state in epithelia and interstitial space of most tissues. In the presence of tissue damage, inflammatory cytokines or pathogens, immature DCs start a differentiation process called maturation and than migrate to lymph nodes, to present the encountered antigen to T cells, thereby inducing a primary or secondary immune response , , . Hallmarks of this maturation process to induce T cell responses are the upregulation of cell surface major histocompatibility complex class I and II and co-stimulatory molecules, such as CD80, CD86, and CD83. Several cytokines, including IL-12, TNF-α, and IL-10 are released by DCs during maturation , , . In most tissues, DCs are present in immature state that lacks the requisite accessory signals for T cell activation . Thus, understanding of DC maturation signals is important for immunotherapeutic protocols of a variety of immune diseases. The inflammatory stimuli, including TNF-α, IL-1β, and lipopolysaccharide (LPS), have been known to enhance antigen presenting ability of T cells in the maturation process of DCs and upregulate production of cytokines, including IL-12 , , . In addition, various factors, such as CD40 ligand, CpG motifs in bacterial DNA, haptens, and apoptotic cells, also have been known to promote the expression of MHC and costimulatory molecules and are responsible for DC maturation , , , . Adhesion molecules play an important role in DC adhesion and migration through receptors . Connective tissue DCs accumulate at sites of extracellular matrix (ECM) deposition and exhibit the binding of ECMs, such as fibronectin, laminin, and collagen through members of integrins , . Several studies have shown that collagen accumulated at the inflammatory areas may play a critical role in regulating the function of DCs. Especially, the engagement of type I collagen (ColI) promotes the expression of co-stimulatory molecules and secretion of cytokines in murine and human DCs , . However, the mechanism of collagen-mediated DC maturation remains to be understood. Although, bone marrow-derived DCs express a typical collagen receptor VLA-2, their maturation by ColI is not inhibited by blocking antibody against β1-integins , , suggesting that the activating effect of collagen is mediated by the different receptors. Recently, Discoidin domain receptors (DDRs), DDR1 and DDR2, have been identified as a novel family of tyrosine kinase receptors for collagen . These receptors are expressed in early embryonic development and many adult tissues. Both receptors are activated by fibrillar collagens (types I, II, and III), but DDR1 can be activated by nonfibrillar collagens (type IV). DDR1 has been found in lung, kidney, breast, and brain tissue, while DDR2 is expressed at highest levels in skeletal muscle, skin, kidney, and lung tissue. DDR1 appears to be a key regulator of cell morphogenesis, differentiation, and proliferation in several organs , and DDR2 is involved in ECM remodeling during morphogenesis and tissue repair . However, the DC activation event mediated by DDRs is not well-understood.