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  • br Integrins Integrins are a large

    2018-11-12


    Integrins Integrins are a large family of receptors which can bind ECM components, soluble extracellular ligands or other membrane bound cell surface molecules. In mammals, there are 24 known heterodimeric integrin receptors comprising of a non-covalent pairing of one of 8 β subunits with one of 18 α subunits. The different heterodimers each have specific ECM binding partners (Table 1) and have been reviewed in detail previously (Berrier and Yamada, 2007; Luo et al., 2007; Humphries et al., 2006; Hynes, 2002). Each subunit has a large extracellular domain and short cytoplasmic fragment (50aa, with the exception of β4 which is about 1000aa) forming a typical type I transmembrane glycoprotein (Hynes, 2002). Some integrin subunits such as β1 are ubiquitously expressed whereas others are expressed in specific tissues or stages of differentiation. For example, β7 is specific to subsets of leukocytes (Humphries et al., 2006; Pribila et al., 2004) and is involved in trafficking of leukocytes to sites of injury or inflammation. Cell surface integrins play a major role in communication between the cytoplasm and extracellular space. Integrins control a whole host of cellular functions through inside-out and outside-in signalling including cell motility, survival, differentiation and proliferation (through interaction with members of the Cyclin family (Docheva et al., 2007)) as well as ECM remodelling (Berrier and Yamada, 2007) and embryonic development (Hynes, 2002; Bouvard et al., 2001) (Fig. 2). The extracellular domain of integrins can bind ECM proteins used in hESC support such as collagen, fibronectin, laminin and vitronectin as well as members of the SIBLING family (Small Integrin Binding Ligand, N-Linked Glycoproteins e.g. osteopontin and bone sialoprotein). Integrins can also associate with receptors on the surface of other JNJ-26481585 through direct interaction with membrane bound proteins such as vascular- or intracellular- cell adhesion molecules (VCAM and ICAM) (Humphries et al., 2006; Docheva et al., 2007; Fisher et al., 2001) or through linker molecules such as von Willebrand factor, which assists in the binding of platelets to one another during blood clotting (Bennett et al., 2009) (Table 1, Fig. 1). Outside-in signalling of integrin receptors through interactions with the ECM generates clustering of integrin heterodimers called focal adhesion sites. Integrin clustering occurs after ECM adhesion promoting lateral association with other cell surface receptors and increases in the cytoplasmic concentration of cell signalling molecules such as PI3-kinase and MEK-ERK, which are already implicated in hESC maintenance (Li et al., 2007; Kang et al., 2005; Pera and Tam, 2010; Armstrong et al., 2006). The focal adhesion sites can recruit over 50 different cytoplasmic proteins to the integrin cytoplasmic domain (Lo, 2006). Proteins recruited comprise of 3 general classes: 1) integrin binding proteins (e.g. talin or focal adhesion kinase), 2) scaffold and adaptor proteins (e.g. those of the cytoskeleton, tensin, vinculin, paxillin and α-actinin) and 3) enzymes that effect downstream signalling to influence cytoskeletal remodelling, cell migration, survival and gene regulation (e.g. tyrosine kinases, serine/threonine kinases, tyrosine phosphatases) although many recruited proteins can be categorised in more than one class (Fig. 2) (Berrier and Yamada, 2007). No enzymatic activity has as yet been identified in the cytoplasmic domains of integrin receptors.
    Integrin Expression During Development Knockout mouse models have allowed examination of the role of almost all known integrin subunits during mammalian embryonic development (Hynes, 2002) (Table 1). Deletion or mutation of specific integrin subunits in mice leads to a wide range of phenotypes in the developing embryo from early lethality to particular organ dysfunction to normal mouse development. For a concise review of these experiments please refer to Bouvard et al., Meighan and Schwarzbauer and Bokel and Brown (Bouvard et al., 2001; Meighan and Schwarzbauer, 2008; Bokel and Brown, 2002). Deletion of β1, a subunit of 12 out of the 24 integrin heterodimers (Table 1) for example leads to failure to implant due to inner cell mass (ICM) deficiencies (Stephens et al., 1995; Fassler and Meyer, 1995). Chimeric mice have been used to study the effects of β1 subunit deficiencies and found effects on multiple cell lineages, tissues and cell functions including haematopoietic stem cell (HSC) homing and migration (Potocnik et al., 2000; Hirsch et al., 1996), impaired vasculogenesis in mouse embryonic stem cells (mESC) (Bloch et al., 1997), reduced proliferation in keratinocytes and cardiac muscle defects (Keller et al., 2001; Baudoin et al., 1998). In addition to the effects of altering β1, here we provide a concise summary of the effects of deleting certain integrins during development and how differentiation of cells to the three somatic lineages; Endoderm, Mesoderm and Ectoderm are affected.