Abstract
The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFκB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Adhesion / genetics
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Cell Adhesion / immunology
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Cell Membrane / genetics
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Lymphocyte Function-Associated Antigen-1 / genetics
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Lymphocyte Function-Associated Antigen-1 / immunology
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Lymphocyte Function-Associated Antigen-1 / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Mutant Strains
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Multiprotein Complexes / genetics
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Multiprotein Complexes / immunology
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Multiprotein Complexes / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / immunology*
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology*
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport / genetics
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Protein Transport / immunology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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rap1 GTP-Binding Proteins / genetics
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rap1 GTP-Binding Proteins / immunology*
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rap1 GTP-Binding Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Fyb protein, mouse
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Lymphocyte Function-Associated Antigen-1
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Membrane Proteins
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Multiprotein Complexes
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Phosphoproteins
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RIAM protein, mouse
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Receptors, Antigen, T-Cell
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SKAP55 protein, mouse
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SLP-76 signal Transducing adaptor proteins
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hematopoietic progenitor kinase 1
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Protein Serine-Threonine Kinases
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rap1 GTP-Binding Proteins