Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2
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Background Shc and Grb2 form a complex in cells in response to growth factor stimulation and link tyrosine kinases to Ras during the resulting signaling process. Shc and Grb2 each contain domains that mediate interactions with other unidentified intracellular proteins. For example, the Shc PTB domain binds to 130 kDa and 145 kDa tyrosine-phosphorylated proteins in response to stimulation of cells by growth factors, cytokines and crosslinking of antigen receptors. The Grb2 SH3 domains bind to an unidentified 116 kDa protein in T cells. We have identified three proteins, of 110 kDa, 130 kDa and 145 kDa, as a new family of molecules encoded by the same gene. In vivo studies show that these proteins form signal transduction complexes with Shc and with Grb2. Results The 130 kDa and 145 kDa tyrosine-phosphorylated proteins that associate with the Shc PTB domain were purified by conventional chromatographic methods. Partial peptide and cDNA sequences corresponding to these proteins, termed SIP-145 and SIP-130 (SIP for signaling inositol polyphosphate 5-phosphatase), identified them as SH2 domain-containing products of a single gene and as members of the inositol polyphosphate 5-phosphatase family. The SIP-130 and SIP-145 proteins and inositol polyphosphate 5-phosphatase activity associated with Shc in vivo in response to B-cell activation. By using an independent approach, expression cloning, we found that the Grb2 SH3 domains bind specifically to SIP-110, a 110 kDa splice variant o…
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We detected several SHIP1 binding partners previously identified in other myeloid cells, such as SH3KBP1, GRB2, SHC1, DOK2, ARAP1, CD2AP.
“We detected several SHIP1 binding partners previously identified in other myeloid cells, such as SH3KBP117, GRB218, SHC118, DOK218,19, ARAP120 and CD2AP21 (Figure 1D).”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [19]
SHIP1 regulates these signaling events by binding to important adaptor proteins in the cytoplasm, such as SHC1, DOK2, GRB2 and others in lymphoid and hematopoietic cells.
“SHIP1 regulates these signaling events by binding to important adaptor proteins in the cytoplasm, such as SHC1, DOK2, GRB2 and others in lymphoid and hematopoietic cells18,19.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [19]
SHIP1 was originally observed in hematopoietic cells after cytokines and growth factors induced tyrosine phosphorylation of this 145-kDa protein.
“SHIP1 was originally observed in hematopoietic cells after a variety of cytokines and growth factors induced the tyrosine phosphorylation of this 145-kDa protein [98–104].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [98]
The C-terminus of SHIP1 contains a NPxY motif that can bind proteins containing ITIM/ITAM, PTB or SH2 domains, and a proline-rich PxxP motif that contains SH3-binding domains.
“The C-terminus of SHIP1 contains a NPxY motif, which can bind to proteins containing immunoreceptor tyrosine inhibitory motifs (ITIM)/immunoreceptor tyrosine activating motifs (ITAM), phosphotyrosine-binding (PTB) or SH2 domains, as well as a proline-rich PxxP motif that contains SH3-binding domains [47, 93–98] (Fig. 2).”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [98]
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- Authors
- Kavanaugh, W. M., Pot, D. A., Chin, S. M., Deuter-Reinhard, M., Jefferson, A. B., Norris, F. A., Masiarz, F. R., Cousens, L. S., Majerus, P. W., & Williams, L. T.
- Affiliations
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Corresponding author
- Williams, Lewis T.
- ORCID
- Pot, D.A.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 1996-04
- Volume
- 6
- Issue
- 4
- Pages
- 438-445
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W1971997730
- Cited by
- 217
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2021: 1 · 2018: 2 · 2017: 1 · 2015: 7 · 2013: 6 · 2012: 6
- FWCI
- 10.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50hl014147-25)
- National Heart, Lung, and Blood Institute (HL-07088, HL-16134, HL14147, T32HL007088)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- inositol polyphosphate 5-phosphatase, Shc, Grb2, splice variants, SH2 domain, SH3 domain, PTB domain, signal transduction, phosphatidylinositol 3,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, B cell activation, Ras signaling, tyrosine phosphorylation
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Amino Acid Sequence, Animals, B-Lymphocytes, Base Sequence, Cell Line, Transformed, Chlorocebus aethiops, Cloning, Molecular, Humans, Lymphocyte Activation, Molecular Sequence Data, Phosphoric Monoester Hydrolases, Proteins, Rabbits, Signal Transduction, Caenorhabditis elegans, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, ErbB Receptors
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