Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

Abstract

IntroductionMast cells are multifunctional hematopoietic cells, important for both innate and specific immunity. 1 Immature mast cells leave the bone marrow to migrate to target tissues, mostly mucosal and connective tissues, where they undergo terminal differentiation and perform their biologic functions. 2 Stem cell factor (SCF) and its receptor Kit are essential for mast cell development in vivo, as shown by the phenotype of mice with null mutations in the Kit (White Spotting or W) or SCF (Steel or Sl) loci. Indeed, these mice lack tissue mast cells and also exhibit defects in hematopoiesis, pigmentation, and reproduction. 3 In bone marrow mast cells (BMMCs), activation of Kit, a type III receptor tyrosine kinase (RTK), stimulates cellular responses such as proliferation, survival, differentiation, chemotaxis, cell adhesion, and degranulation. 4 Upon SCF binding, the Kit receptor dimerizes, autophosphorylates, and subsequently transphosphorylates specific tyrosines (Y). The resulting phosphotyrosine (pY) residues serve as docking sites for Src homology 2 (SH2) domain-containing proteins, which control intracellular signaling pathways such as all 3 mitogen-activated protein kinases (MAPKs; ERK, p38, and c-jun N-terminal kinase [JNK]), phosphatidylinositol 3-kinase (PI-3K), and Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathways. 4,5 Recruitment of particular targets is mediated by the ability of SH2 domains to recognize specific pY-containing motifs on the activated receptor. Analyses of individual docking sites on Kit have provided valuable information about the activation of pathways emanating from this receptor. 6 Juxtamembrane Y567 and Y569 are critical recruitment sites for different regulatory signaling molecules. These include activators such as Src family kinases (Fyn and Lyn), Shp-2 phosphatase and Shc adaptor protein, or negative modulators such as Shp-1 phosphatase, Csk-homology kinase (Chk), suppressors of cytokine signaling (SOCS) proteins, and APS adaptor protein. 5,7,8 Mutational and "knock-in" studies on Kit Y567/Y569 have revealed their important role in cell development, proliferation, survival, and migration. 6,9-11 However, the biologic significance of these interactions is still poorly understood.Lnk is a member of the adaptor protein family that includes APS and SH2-B. All 3 members share common protein-protein interaction domains and motifs: a dimerization domain at the aminoterminus, a pleckstrin homology (PH) domain, an SH2 domain, and a conserved tyrosine near the carboxy-terminus. 12 Mice deficient for members of this family have demonstrated the positive (SH2-B) and negative (Lnk and APS) role of these adaptors in growth factor, cytokine, and antigen-receptor signaling. [13][14][15][16][17][18] In particular, Lnk nullizygous mice show mainly a profound perturbation in hematopoiesis. These animals exhibit splenomegaly together with fibrosis, expansion of hematopoietic stem cells (HSCs), and myeloid and B lymphoid progenitors. [17][18][19] Recent ana...

A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase

“…Lymphocytespecific adaptor protein Lnk also plays an important role in c-Kit downregulation. Lnk preferentially binds to the juxtamembrane region of c-Kit, suppressing the intrinsic c-Kit catalytic activity [34]. In addition, c-Kit signalling can be negatively regulated by Src homology region 2 domaincontaining phosphatase-1 (SHP-1) through receptor tyrosine dephosphorylation [35].…”

Lnk Deletion Reinforces the Function of Bone Marrow Progenitors in Promoting Neovascularization and Astrogliosis Following Spinal Cord Injury

“…Lnk was reported to negatively regulate SCF/c-Kit signaling in B cell progenitors, hematopoietic stem/progenitor cells, and mast cells [10,13,29]. Lnk is furthermore considered to negatively regulate endothelial cell derived hematopoiesis during embryonic development [30].…”

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

“…The fist identified binding partner of the Lnk protein was the SCF receptor, Kit. The primary Kitbinding site for Lnk SH2 domain has been identified as phosphotyrosine 567 (pTyr567), which resides in the juxtamembrane region of the receptor (Simon et al, 2008;Gueller et al, 2008). Similarly, the SH2 domain of APS was reported to bind to Y568 and Y936 in the human c-Kit receptor (Wollberg et al, 2003).…”