Regulation of WASp by phosphorylation

Figures & data

Figure 1 A model for the regulation of WASp by phosphorylation. The folded, inactive WASp molecule can be recruited to areas of receptor signalling via SH3 domain-containing adaptors (e.g., Nck) (A), were it can be activated by Cdc42 and PtdIns(4,5)P₂ and phosphorylated by a kinase, such as Src (B). Once Cdc42 activity is terminated, the phosphorylated species (C) may be dephosphorylated by a phosphatase and go through further rounds of activation (A) or it may be proteolytically degraded (D). Alternatively, the phosphorylated species, may, in the absence of Cdc42 binding, refold and thus be “primed” (E) for activation by signals other than Cdc42, such as binding by SH2- and SH3 domain—containing proteins, and thus become active once again (F).

Table 1 Stimuli inducing WASp phosphorylation in cells

Cell type	Stimulus	Kinase	Effect	Reference
B cells	B cell receptor ligation	Btk	protein association	Baba et al.18
platelets	thrombin, thrombin + collagen, integrin αIIbβ3—dependent	n.d.	WASp degradation	Lutskiy et al.34
platelets	collagen	n.d.	WASp degradation (?)	Oda et al.37
natural killer cells	β2 integrin and CD16 clustering	n.d.	actin polymerisation (?)	Gismondi et al.38
mast cells	FcɛR clustering	Btk, Lyn	n.d.	Guinamard et al.39
macrophages	FcγR-mediated phagocytosis	n.d.	phagocytosis	Park & Cox23
platelets	Mn^2+/fibrinogen, integrin αIIbβ3—dependent	Btk, Syk	cell spreading	Soriani et al.40
platelets	CD32 cross-linking	Syk (?)	n.d.	Oda et al.41
platelets	collagen-related peptide binding to Glycoprotein VI	Btk (?)	n.d.	Gross et al.42
T cells	T cell receptor engagement	Fyn	actin polymerization, synapse formation	Badour et al.22
osteoclasts	osteopontin binding to αvβ3 integrin	c-Src (?)	n.d.	Chellaiah et al.43

Baba Y, Nonoyama S, Matsushita M, Yamadori T, Hashimoto S, Imai K, et al. Involvement of wiskottaldrich syndrome protein in B-cell cytoplasmic tyrosine kinase pathway. Blood 1999; 93:2003 - 2012

 PubMed Web of Science ®Google Scholar

Lutskiy MI, Shcherbina A, Bachli ET, Cooley J, Remold-O’Donnell E. WASP localizes to the membrane skeleton of platelets. Br J Haematol 2007; 139:98 - 105

 PubMed Web of Science ®Google Scholar

Oda A, Ochs H, Druker BJ, Ozaki K, Watanabe C, Handa M, et al. Collagen induces tyrosine phosphorylation of Wiskott-Aldrych Syndrome protein in human platelets. Blood 1998; 92:1852 - 1858

 PubMed Web of Science ®Google Scholar

Gismondi A, Cifaldi L, Mazza C, Giliani S, Parolini S, Morrone S, et al. Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Blood 2004; 104:436 - 443

 PubMed Web of Science ®Google Scholar

Guinamard R, Aspenström P, Fougereau M, Chavrier P, Guillemot J-C. Tyrosine phosphorylation of the Wiskott-Aldrich Syndrome protein by Lyn and Btk is regulated by CDC42. FEBS Lett 1998; 434:431 - 436

 PubMed Web of Science ®Google Scholar

Park H, Cox D. Cdc42 Regulates Fc? receptor-mediated phagocytosis through the activation and phosphorylation of Wiskott-Aldrich Syndrome Protein (WASP) and Neural-WASP. Mol Biol Cell 2009; 20:4500 - 4508

 PubMed Web of Science ®Google Scholar

Soriani A, Moran B, De Virgilio M, Kawakami T, Altman A, Lowell C, et al. A role for PKCϑ in outside-in αIIbβ3 signaling. J Thromb Hemost 20 2006; 4:648 - 655

 PubMed Web of Science ®Google Scholar

Oda A, Ochs H, Lasky LA, Spencer S, Ozaki K, Fujihara M, et al. CrkL is an adapter for Wiskott-Aldrich syndrome protein. Blood 2001; 97:2633 - 2639

 PubMed Web of Science ®Google Scholar

Gross BS, Wilde JI, Quek L, Chapel H, Nelson DL, Watson SP. Regulation and Function of WASp in Platelets by the Collagen Receptor, Glycoprotein VI. Blood 1999; 94:4166 - 4176

 PubMed Web of Science ®Google Scholar

Badour K, Zhang J, Shi F, Leng Y, Collins M, Siminovitch KA. Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich Syndrome Protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J Exp Med 2004; 199:99 - 111

 PubMed Web of Science ®Google Scholar

Chellaiah MA, Kuppuswamy D, Lasky L, Linder S. Phosphorylation of a Wiscott-Aldrich Syndrome Protein-associated signal complex is critical in osteoclast bone resorption. J Biol Chem 2007; 282:10104 - 10116

 PubMed Web of Science ®Google Scholar