Association of signal-regulatory proteins beta with KARAP/DAP-12

The signal-regulatory proteins (SIRP) are Ig-like cell surface receptors de tected in hematopoietic and non-hematopoietic cells. SIRP are classified as SIRP alpha molecules, containing a 110- to 113-amino acid long, or SIRP be ta molecules, with a 5-amino acid long intracytoplasmic domain, SIRP alpha molecules belong to inhibitory immunoreceptor tyrosine-based inhibition mot if (ITIM)-bearing molecules. The majority of ITIM-bearing receptors are pai red with activating isoforms, which share highly related extracytoplasmic d omains but harbor a shorter cytoplasmic domain devoid of ITIM and contain a charged amino acid residue in their transmembrane domain. Activating recep tors are associated with immunoreceptor tyrosine-based activation motif (IT AM)-bearing proteins, such as KARAP/DAP-12 and FcR gamma. In this report, w e show that human SIRP beta 1 is included in an oligomeric complex with KAR AP/DAP-12 in hematopoietic and non-hematopoietic transfectant cells as well as in human monocytes. The physical association between SIRP beta 1 and KA RAP/DAP-12 results in the functional coupling of SIRP beta 1 engagement to the recruitment of the protein tyrosine kinase Syk and to serotonin release in RBL cell transfectants. Therefore our results show that SIRP beta 1 act s as an activating isoform of SIRP alpha. molecules, confirming the co-exis tence of inhibitory ITIM-bearing molecules, recruiting SHP-1 and SHP-2 prot ein tyrosine phosphatases, and activating counterparts, whose engagement co uples to protein tyrosine kinases via ITAM-bearing molecules.