Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

Abstract

Insulin receptor (IR) and class I major histocompatibility complex molecules associate with one another in cell membranes, but the functional consequences of this association are not defined. We found that IR and human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the presence of free HLA heavy chains. All of the effects noted were reduced or abrogated if liposomes or cells were incubated with excess HLA-I light chain, ␤2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphorylated on tyrosine and associated with phosphoinositide 3-kinase when B-LCL were stimulated with insulin. INTRODUCTIONThe manifold effects of insulin on cell physiology are mediated by a specific insulin receptor (IR). Insulin binding triggers a conformational change in IR, stimulating its tyrosine kinase activity and leading to its autophosphorylation (Rosen, 1987;White and Kahn, 1994). The insulin signal is propagated downstream of the IR kinase by the binding and tyrosine phosphorylation of docking proteins that connect IR to signaling pathways by mediating the binding of intracellular signaling proteins (Backer et al., 1992;Kuhne et al., 1993;Myers et al., 1994).IR has been shown to associate with other proteins in the plane of the plasma membrane. Some of these associations, i.e., with PC-1, a transmembrane glycoprotein (Maddux et al., 1995) and with ␤ adrenergic receptors (Karoor, et al., 1995;Baltensperger, et al., 1996), clearly have functional consequences. The first affects the kinase activity of IR, and the second affects the function of ␤ adrenergic receptors. In contrast, no functional effects have been clearly shown for another lateral association of IR, i.e., that with the major histocompatibility complex (MHC) I molecules, mouse H2 and human HLA. Although the association of IR with these molecules has been demonstrated using biophysical and biochemical techniques (Fehlmann et al., 1985a;Phillips et al., 1986;Edidin and Reiland, 1990;Liegler et al., 1991), there is little evidence that this association has functional consequences for either IR or MHC I molecules. At best, some studies correlate MHC phenotype with insulin binding and signaling activity (Lafuse and Edidin, 1980;Kittur et al., 1987;Edidin, 1988), but others do not (Verland et al., 1989;Liegler et al., 1991). Thus the consequences, if any, of the association between IR and MHC I molecules remain unclear.We have used a two-part strategy to detect the formation of molecular complexes between IR and human MHC I molecules, HLA, and to measure the functional consequences of this association for insulinmediated signaling and the state of MHC phosphorylati...

Immune Privilege Revisited: The Roles of Neuronal MHC Class I Molecules in Brain Development and Plasticity

“…The best characterized non-immune interaction of MHC class I is with the IR. It has been suggested that MHC class I molecules are involved in glycosylation of IR and its proper transport to the cell surface, but most evidence has been provided for the role of MHC class I in insulin-induced IR internalization (Olsson et al 1994, Ramalingam et al 1997, Stagsted 1998, Stagsted et al 1993a, Stagsted et al 1990, Stagsted et al 1993b. A number of studies have suggested that MHC class I associates with IR after insulin binding thereby causing its internalization and removal from the cell surface.…”

“…characterized by a low basal transmission which is www.intechopen.com maintained by activation of a number of receptors that have inhibitory effects on synaptic transmission (Nicoll and Schmitz 2005). As previously mentioned, given that the best characterized non-immune function of MHC class I is regulation of trafficking and internalization of various receptors (Olsson et al 1994, Stagsted 1998, Stagsted et al 1990, Ramalingam et al 1997, it is likely that neuronal MHC class I molecules in the marmoset hippocampus are needed for proper internalization of one or several of those receptors (Figure 8). One may speculate that blocking the interaction of MHC class I with such Fig.…”

Lack of Tyrosine 320 Impairs Spontaneous Endocytosis and Enhances Release of HLA-B27 Molecules

“…M ajor histocompatibility complex class I (MHC-I) 3 molecules are trimeric structures of a 44-to 49-kDa H chain, a 12-kDa L chain named ␤ 2 -microglobulin (␤ 2 m), and a 9-to 11-aa peptide. MHC-I molecules are folded and assembled inside the endoplasmic reticulum (ER) with the aid of several chaperones and accessory molecules such as calnexin, calreticulin, tapasin, and ERp57, and are ultimately transported to the cell surface of almost all nucleated cells (1).…”

“…MHC-I molecules are folded and assembled inside the endoplasmic reticulum (ER) with the aid of several chaperones and accessory molecules such as calnexin, calreticulin, tapasin, and ERp57, and are ultimately transported to the cell surface of almost all nucleated cells (1). In addition to their role in presenting peptides to CD8 ϩ CTLs, cell surface MHC-I molecules have been implicated in receptor-mediated endocytosis (2)(3)(4).…”

Alterations in the Expression of MHC Class I Glycoproteins by B16BL6 Melanoma Cells Modulate Insulin Receptor-Regulated Signal Transduction and Augments Resistance to Apoptosis

“…It has been reported in a number of studies that direct interactions between MHC glycoproteins and the IR were found to enhance ligand-induced internalization of the receptor (18). Other investigators have shown that the ratio between membrane-expressed MHC class I glycoproteins and IR molecules determines the extent of ligand-induced phosphorylation of the IR and the IR substrate-1 and, as well, the recruitment of phosphatidylinositol 3-kinase to the plasma membrane (11). The aforementioned findings suggest that MHC class I glycoproteins may play an important role in growth factor-mediated cell-cell communication and in receptor-mediated signal transduction; both of these processes are significantly impaired during malignant transformation and tumor progression.…”