SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages.
Inhibitory immunoreceptors downregulate signaling by recruiting Src homology 2 (SH2) domain-containing tyrosine and/or lipid phosphatases to activating receptor complexes [1]. There are indications that some inhibitory receptors might also perform other functions [2] [3]. In adherent macrophages, two inhibitory receptors, SHPS-1 and PIR-B, are the major proteins binding to the tyrosine phosphatase SHP-1. SHPS-1 also associates with two tyrosine-phosphorylated proteins (pp55 and pp130) and a protein tyrosine kinase [4]. Here, we have identified pp55 and pp130 as the adaptor molecules SKAP55hom/R (Src-kinase-associated protein of 55 kDa homologue) and FYB/SLAP-130 (Fyn-binding protein/SLP-76-associated protein of 130 kDa), respectively, and the tyrosine kinase activity as PYK2. Two distinct SHPS-1 complexes were formed, one containing SKAP55hom/R and FYB/SLAP-130, and the other containing PYK2. Recruitment of FYB/SLAP-130 to SHPS-1 required SKAP55hom/R, whereas PYK2 associated with SHPS-1 independently. Formation of both complexes was independent of SHP-1 and tyrosine phosphorylation of SHPS-1. Finally, tyrosine phosphorylation of members of the SHPS-1 complexes was regulated by integrin-mediated adhesion. Thus, SHPS-1 provides a scaffold for the assembly of multi-protein complexes that might both transmit adhesion-regulated signals and help terminate such signals through SHP-1-directed dephosphorylation. Other inhibitory immunoreceptors might have similar scaffold-like functions.
Timms
J F
JF
Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Swanson
K D
KD
Marie-Cardine
A
A
Raab
M
M
Rudd
C E
CE
Schraven
B
B
Neel
B G
BG
D000818:Animals; D000943:Antigens, Differentiation; D001854:Bone Marrow Cells / Q000737:chemistry*; D019556:COS Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015151:Immunoblotting; D008264:Macrophages / Q000737:chemistry* / Q000187:drug effects; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D017510:Protein Folding; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D011971:Receptors, Immunologic; D013450:Sulfones / Q000032:analysis / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism
D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D009687:Nuclear Proteins; D010750:Phosphoproteins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D013450:Sulfones; C095383:nucleolar phosphoprotein p130; C081650:5'-O-(((2-decanoylamino-3-phenylpropyloxycarbonyl)amino)sulfonyl)uridine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; D014529:Uridine