Genetic evidence for convergence of c-Kit– and α4 integrin–mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells

Abstract

IntroductionMigration of hematopoietic stem and progenitors cells during embryogenesis, retention of these cells in the adult bone marrow microenvironment, and the distribution of committed progenitors to various adult tissues under steady state conditions or during inflammation are regulated in part by adhesion receptors, including integrins. 1-3 However, our current understanding of integrindirected (haptotactic) migration/homing of hematopoietic cells and the potential impact of concurrent stimulation by growth factors on haptotactic migration is limited. Further, the biochemical pathways that regulate haptotaxis in primitive or mature hematopoietic cells are largely unknown.Integrins are a family of heterodimeric transmembrane glycoproteins that can function as cell-extracellular matrix (ECM) or cell-cell adhesion receptors. 3 The ␣ 4 integrins are particularly important owing to their involvement in various developmental and physiologic processes. 4,5 The ␣ 4 chain can associate with either of the 2 ␤ chains, ␤ 1 and ␤ 7 . The ␣ 4 ␤ 1 mediates adhesion to vascular cell adhesion molecule-1 (VCAM-1) and to the alternatively spliced CS-1 region of fibronectin. In contrast, ␣ 4 ␤ 7 predominantly mediates adhesion to mucosal addressin cell adhesion molecule-1 (MAdCAM-1). 6,7 Mast cells are bone marrow (BM)-derived cells that play an essential role in normal host defense and various allergic diseases. [8][9][10] Mast cells are recruited into tissues by the release of their precursors from the bone marrow into the peripheral blood, followed by the migration of these precursors into various tissues, including mucosal and connective tissues. [8][9][10][11][12] Mast cells express ␤ 1 and ␤ 7 integrins, and ligation of these integrin receptors modulates mast cell functions. 13 In vivo, functional blockade of ␣ 4 integrin inhibits mast cell activation in a rat model of airway hyperresponsiveness, owing in part to impaired migration of these cells to the sites of airway inflammation. 14 Further, mast cells isolated following an intestinal nematode infection express high levels of ␣ 4 ␤ 7 integrin, while mast cells isolated from peritoneal cavity express mainly ␣ 4 ␤ 1 . 15 Thus, integrins may be differentially expressed by mast cells in response to environmental cues. Alternatively, selective expression of integrins might occur during the development of different mast cell subtypes, which could dictate the migration of committed mast cell precursors to appropriate tissues. 16 Recently, Gurish et al, 13 using ␤ 7 integrin-deficient mice, demonstrated a critical role for ␣ 4 ␤ 7 in the migration of mast cells to the small intestine, but not to other tissues. Along with a specific role for ␣ 4 ␤ 7 , a role for the c-Kit receptor in migration of mast cell progenitors to the small intestine was suggested. 13 Interestingly, similar to the mast cell deficiency seen in ␤ 7 integrin-deficient mice, mutations in the c-Kit receptor or its ligand, stem cell factor (SCF), are also associated with reduced intestinal mast cell progeni...

The Scaffolding Adapter Gab2, via Shp-2, Regulates Kit-evoked Mast Cell Proliferation by Activating the Rac/JNK Pathway

“…PI3K can activate Rac through Rac GEF (17). PI3K via activation of Rac also mediates SCF-evoked mast cell migration (18). However, it is not clear what molecule mediates the activation of Rac by SFK from Kit Tyr 567 .…”

FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

“…A number of key signaling proteins are required for SCF to trigger mast cell migration downstream of c-KIT, including class IA phosphoinositide 3-kinase, Rac GTPases, and FYN kinase (25,42,50,51). FES kinase also plays a significant role in BMMCs (22) and in tumor-associated mast cells (this study) and macrophages (24).…”

“…1A and involves addition of BMMCs that were starved of cytokines to wells containing fibronectin-coated glass coverslips on which an agarose drop (with or without SCF) resides. KIT signaling to b1 integrins promotes adhesion of mast cells (42), and this was reflected in formation of a ring of BMMCs surrounding the edge of the SCF-embedded agarose drops (Fig. 1B).…”

Rac2-Deficient Hematopoietic Stem Cells Show Defective Interaction with the Hematopoietic Microenvironment and Long-Term Engraftment Failure

“…In addition, in some cells, both integrins and growth factor receptors have been shown to transduce signals that converge on Rho GTPases, leading to cross-talk between these surface receptors [19,[47][48][49]. Such converging signals lead to migration of mast cells on fibronectin after stimulation by stem cell factor (SCF) via activation of Vav, a guanine exchange factor (GEF) for Rac, and subsequent Rac activation [19].…”

“…These same receptors may also initiate signaling pathways following adhesion [19]. The heterodimeric beta-1 integrins, particularly the α4β1 (VLA-4) and α5β1 (VLA-5) integrins, and the adhesion molecule CD44 appear to be of critical importance for homing and localization of HSC to the hematopoietic microenvironment [20][21][22][23][24][25][26][27] mediating binding to fibronectin, as well as the vascular cell adhesion molecule (VCAM-1) [28,29] and proteoglycans.…”