Analysis of Ig-alpha-tyrosine kinase interaction reveals two levels of binding specificity and tyrosine phosphorylated Ig-alpha stimulation of Fyn activity.
The B cell antigen receptor complex (BCR) is composed of membrane Ig and heterodimers of Ig-alpha and Ig-beta/gamma. Recent findings indicate that Ig-alpha associates with Src-family kinases, including Fyn and Lyn, via an approximately 26 amino acid motif termed ARH1. Studies reported here (i) define two mechanisms whereby this motif binds Fyn and (ii) reveal an important functional consequence of binding, i.e. kinase activation. Mutational analysis indicates that specific low-affinity binding is determined by a short sequence, -DCSM-, in the motif and is not dependent on motif tyrosine residues. In contrast, the doubly tyrosine phosphorylated motif binds independently of DCSM and with high affinity. Importantly, this binding leads to Fyn activation. Taken together with studies which map low-affinity binding of Fyn or Lyn to the kinase's N-terminal unique region and high-affinity binding to the kinase's SH2 domain, these results suggest a mechanism of BCR activation in which the non-phosphorylated resting receptor is associated with Src-family kinases and, upon stimulation, tyrosine phosphorylation of Ig-alpha leads to reorientation and activation of receptor-associated kinases.
Clark
M R
MR
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO.
Johnson
S A
SA
Cambier
J C
JC
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn