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Publication Detail
Identification of major binding proteins and substrates for the SH2- containing protein tyrosine phosphatase SHP-1 in macrophages
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Timms JF, Carlberg K, Gu H, Chen H, Kamatkar S, Nadler MJ, Rohrschneider LR, Neel BG
  • Publication date:
  • Pagination:
    3838, 3850
  • Journal:
    Molecular and Cellular Biology
  • Volume:
  • Issue:
  • Status:
  • Print ISSN:
  • Keywords:
    src Homology Domains, Animal, Histocompatibility Antigens, metabolism, Macrophages, Mice, Inbred C3H, Inbred C57BL, Nerve Tissue Proteins, Phosphorylation, Phosphotyrosine, Protein-Tyrosine-Phosphatase, genetics, Receptors, Macrophage Colony-Stimulating Factor, Recombinant Fusion Proteins, Substrate Specificity, Support, U.S.Gov\'t, P.H.S., Animal, data, EXPRESSION, Glycoproteins, OnCite, Proteins, src Homology Domains
  • Notes:
    Label: 98298228
The protein tyrosine phosphatase SHP-1 is a critical regulator of macrophage biology, but its detailed mechanism of action remains largely undefined. SHP-1 associates with a 130-kDa tyrosyl- phosphorylated species (P130) in macrophages, suggesting that P130 might be an SHP-1 regulator and/or substrate. Here we show that P130 consists of two transmembrane glycoproteins, which we identify as PIR- B/p91A and the signal-regulatory protein (SIRP) family member BIT. These proteins also form separate complexes with SHP-2. BIT, but not PIR-B, is in a complex with the colony-stimulating factor 1 receptor (CSF-1R), suggesting that BIT may direct SHP-1 to the CSF-1R. BIT and PIR-B bind preferentially to substrate-trapping mutants of SHP-1 and are hyperphosphorylated in macrophages from motheaten viable mice, which express catalytically impaired forms of SHP-1, indicating that these proteins are SHP-1 substrates. However, BIT and PIR-B are hypophosphorylated in motheaten macrophages, which completely lack SHP- 1 expression. These data suggest a model in which SHP-1 dephosphorylates specific sites on BIT and PIR-B while protecting other sites from dephosphorylation via its SH2 domains. Finally, BIT and PIR- B associate with two tyrosyl phosphoproteins and a tyrosine kinase activity. Tyrosyl phosphorylation of these proteins and the level of the associated kinase activity are increased in the absence of SHP-1. Our data suggest that BIT and PIR-B recruit multiple signaling molecules to receptor complexes, where they are regulated by SHP-1 and/or SHP-2.
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