Characterization of Cbl-Nck and Nck-Pak1 interactions in myeloid FcγRII signaling

Kayvon D. Izadi, Anat Erdreich-Epstein, Yenbou Liu, Donald L. Durden

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Fc receptors modulate inflammatory processes, including phagocytosis, serotonin and histamine release, superoxide production, and secretion of cytokines. Aggregation of FcγRIIa, the low-affinity receptor for monomeric IgG, activates nonreceptor protein tyrosine kinases such as Lyn, Hck, and Syk, potentially driving the phosphorylation of the downstream adaptor proteins, including Cbl and/or Nck. Previous work from our laboratory using interferonγ-differentiated U937 (U937IF) myeloid cells investigated mechanisms which regulate Fcγ receptor-induced assembly of adaptor complexes. Herein we report that FcγRII receptor signaling in U937IF and HEL cells involves Cbl and Nck, suggesting that Cbl-Nck interactions may link FcγRII to downstream activation of Pak kinase. FcγRII crosslinking induced the phosphorylation of Cbl and Nck on tyrosine. The αCbl immunoprecipitations revealed constitutive binding of Nck and Grb2 to Cbl and FcγRII-inducible binding of CrkL to Cbl. The interactions of Cbl with Nck and CrkL were phosphorylation dependent since dephosphorylation of cellular proteins with potato acid phosphatase abrogated binding. GST-Nck fusion protein pulldown experiments show that Cbl and Pak1 bind to the second SH3 domain of Nck. A specific Src inhibitor, PP1, was shown to completely abrogate the FcγR-induced superoxide response, correlating with a decrease in Chl and Nck tyrosine phosphorylation. Our results provide the first evidence that Src is required for FcγR activation of the respiratory burst in myeloid cells and suggest that Cbl-Nck, Cbl-Pak1, and Nck-Pak1 interactions may regulate this response.

Original languageEnglish (US)
Pages (from-to)330-342
Number of pages13
JournalExperimental Cell Research
Issue number2
StatePublished - Dec 15 1998
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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