Disease relevance of SH3BP2

• Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism [1].
• Here we show that 3BP2 is tyrosine phosphorylated following BCR aggregation on B lymphoma cells, and that 3BP2 is a substrate for Syk and Fyn, but not Btk [2].

High impact information on SH3BP2

• Mutations in the SH3-domain binding protein 2 (SH3BP2) are known to cause a rare childhood disorder called cherubism that is characterized by inflammation and bone loss in the jaw, but the mechanism has remained unclear [3].
• Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism [1].
• Thus, 3BP2 is an important adaptor that may couple activated Zap-70/Syk to a LAT-containing signaling complex involved in TCR-mediated gene transcription [4].
• Adaptor function for the Syk kinases-interacting protein 3BP2 in IL-2 gene activation [4].
• 3BP2 was selectively expressed in hematopoietic/lymphoid tissues and bound via its SH2 domain activated Syk-family kinases in mammalian cells, including in antigen receptor-stimulated T cells [4].

Chemical compound and disease context of SH3BP2

• We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw [5].

Biological context of SH3BP2

• The adaptor 3BP2/SH3BP2, an Abl Src homology domain 3 (SH3)-binding and Syk-kinases interacting protein, exhibits positive regulatory roles in T, natural killer (NK), and basophilic cells [2].
• No evidence was found to indicate that SH3BP2 is the tumor suppressor gene at 4p16.3 involved in bladder cancer [6].
• Identification and characterization of the human homologue of SH3BP2, an SH3 binding domain protein within a common region of deletion at 4p16.3 involved in bladder cancer [6].
• Recent studies have revealed the point mutations in the SH3BP2 gene on chromosome 4p16.3 in cherubism families [7].
• CONCLUSIONS: The missense mutation Pro418Arg was identified in the SH3BP2 gene from a nonfamilial case of cherubism [7].

Anatomical context of SH3BP2

• Furthermore, overexpression and RNAi blocking experiments showed that 3BP2 regulated BCR-mediated activation of nuclear factor of activated T cells (NFATs) [2].
• To further explore the function of 3BP2 in B cells, we screened a yeast 2-hybrid B-lymphocyte library and found 3BP2 as a binding partner of Vav proteins [2].
• To examine the role of 3BP2 in mast cells, we overexpressed the SH2 domain of 3BP2 in the RBL-2H3 cells [8].
• CD244-3BP2 interaction was direct and regulated by phosphorylation, as shown by a three-hybrid analysis in yeast and NK cells [9].
• The adapter 3BP2: how it plugs into leukocyte signaling [10].

Associations of SH3BP2 with chemical compounds

• Tyrosine phosphorylation of adaptor protein 3BP2 induces T cell receptor-mediated activation of transcription factor [11].
• Although mutation of Tyr337 to phenylalanine abrogated human 3BP2 binding, we still observed SAP association, indicating that this motif is not essential for SAP recruitment [9].
• In addition, proline-rich region of 3BP2 bound to the Lyn-SH3 domain [12].
• We identified residues Ser(225) and Ser(277) of 3BP2 as being essential for interaction with 14-3-3 family proteins, optimal 3BP2 serine phosphorylation, and then for 3BP2-dependent function [13].

Physical interactions of SH3BP2

• 3BP2 interacts with human but not murine CD244 [9].
• We also identify p95(vav) and phospholipase C-gamma isoforms as binding partners of 3BP2 [14].
• We have determined high-resolution crystal structures of the complexes between the SH3 domains of Abl and Fyn tyrosine kinases, and two ten-residue proline-rich peptides derived from the SH3-binding proteins 3BP-1 and 3BP-2 [15].

Regulatory relationships of SH3BP2

• CD244 ligation induced 3BP2 phosphorylation and Vav-1 recruitment [9].
• In this context, disturbed PTHrP - PTHrP receptor interaction induced by the mutation in SH3BP2 is discussed [16].

Other interactions of SH3BP2

• 3BP2 also interacted with other components of the BCR signaling pathway, including Syk and phospholipase C gamma (PLC-gamma) [2].
• This suggests the presence of an intermediate molecule between activated CR2 and tyrosine-phosphorylated p95, which may be 3BP2 [17].
• When binding to variant phosphopeptides based on this membrane-distal tyrosine was tested, altering the amino acids immediately following the phosphotyrosine could selectively abolish the interaction with Shc or Grb2, or the binding to both Grb2 and 3BP2 [18].
• Tyr337 on CD244, part of a consensus motif for SAP/SH2 domain protein 1A binding, was critical for the 3BP2 interaction [9].
• We previously showed that the cytoplasmic adapter 3BP2 (also known as SH3BP2) promotes NFAT/AP-1 transcriptional activities in T cells through the activation of Ras- and calcineurin-dependent pathways [13].

Analytical, diagnostic and therapeutic context of SH3BP2

• In the present study, we used direct sequence analysis of the SH3BP2 gene of several individuals from a family with cherubism to search for additional SH3BP2 mutations resulting in cherubism [19].

References