A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain- containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion

Second Department of Internal Medicine, Kobe University School of Medicine, Chuo-ku, Japan.
Molecular and Cellular Biology (Impact Factor: 4.78). 01/1997; 16(12):6887-99. DOI: 10.1128/MCB.16.12.6887
Source: PubMed


Protein tyrosine phosphatases (PTPases), such as SHP-1 and SHP-2, that contain Src homology 2 (SH2) domains play important roles in growth factor and cytokine signal transduction pathways. A protein of approximately 115 to 120 kDa that interacts with SHP-1 and SHP-2 was purified from v-src-transformed rat fibroblasts (SR-3Y1 cells), and the corresponding cDNA was cloned. The predicted amino acid sequence of the encoded protein, termed SHPS-1 (SHP substrate 1), suggests that it is a glycosylated receptor-like protein with three immunoglobulin-like domains in its extracellular region and four YXX(L/V/I) motifs, potential tyrosine phosphorylation and SH2-domain binding sites, in its cytoplasmic region. Various mitogens, including serum, insulin, and lysophosphatidic acid, or cell adhesion induced tyrosine phosphorylation of SHPS-1 and its subsequent association with SHP-2 in cultured cells. Thus, SHPS-1 may be a direct substrate for both tyrosine kinases, such as the insulin receptor kinase or Src, and a specific docking protein for SH2-domain-containing PTPases. In addition, we suggest that SHPS-1 may be a potential substrate for SHP-2 and may function in both growth factor- and cell adhesion-induced cell signaling.

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    The EMBO Journal 02/2015; 34(6). DOI:10.15252/embj.201490563 · 10.43 Impact Factor
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    • "The regulation of all these cellular functions by SIRPα has been attributed to its extracellular binding interactions with the ligand CD47, another important cell surface protein broadly expressed on most cells, and to the SIRPα ITIMs-mediated intracellular signaling. It has been suggested that the extracellular binding of SIRPα to CD47 triggers tyrosine phosphorylation in its cytoplasmic ITIMs, resulting in the association of the SH2 domain-containing protein tyrosine phosphatase (SHP-1 or 2), which consequently initiates negative signaling events leading to the inhibition of cell function [11-16]. Studies of macrophage phagocytosis indicate that ligation of macrophage SIRPα by CD47 expressed on the encountered cells prohibits macrophage phagocytosis, whereas failure of SIRPα engagement by CD47, or deficiency of SIRPα ITIM-mediated signaling, promotes macrophage engulfment of the cell [2,8,17-22]. "
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    ABSTRACT: SIRPα, an ITIMs-containing signaling receptor, negatively regulates leukocyte responses through extracellular interactions with CD47. However, the dynamics of SIRPα-CD47 interactions on the cell surface and the governing mechanisms remain unclear. Here we report that while the purified SIRPα binds to CD47 and that SIRPα is expressed on monocytes and monocytic THP-1 or U937, these SIRPα are ineffective to mediate cell binding to immobilized CD47. However, cell binding to CD47 is significantly enhanced when monocytes transmigrating across endothelia, or being differentiated into macrophages. Cell surface labeling reveals SIRPα to be diffused on naïve monocytes but highly clustered on transmigrated monocytes and macrophages. Protein crosslink and equilibrium centrifugation confirm that SIRPα in the latter cells forms oligomerized complexes resulting in increased avidity for CD47 binding. Furthermore, formation of SIRPα complexes/clusters requires the plasma membrane 'lipid rafts' and the activity of Src family kinase during macrophage differentiation. These results together suggest that 'clustering' SIRPα into plasma membrane microdomains is essential for activated monocytes and macrophages to effectively interact with CD47 and initiate intracellular signaling.
    PLoS ONE 10/2013; 8(10):e77615. DOI:10.1371/journal.pone.0077615 · 3.23 Impact Factor
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    • "SIRP proteins belong to the Ig family of cell surface glycoproteins, where the first member identified was SIRPí µí»¼ (also known as SHPS-1, CD172a, BIT, MFR, or P84) [39] [40] [41] [42] [43] [44]. SIRPí µí»¼ is highly expressed in myeloid cells and neurons, but also in endothelial cells and fibroblasts, and has three extracellular Ig-like domains, one distal IgV-like domain, and two membrane proximal IgC-like domains [41] [42]. In addition, an alternatively spliced form having only one IgV domain has also been reported [45]. "
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    01/2013; 2013(5):614619. DOI:10.1155/2013/614619
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