Cross-talk between α4β1/α5β1 and c-Kit results in opposing effect on growth and survival of hematopoietic cells via the activation of focal adhesion kinase, mitogen-activated protein kinase, and Akt signaling pathways

Abstract

IntroductionAdhesive interactions between hematopoietic progenitor and stem cells and the hematopoietic microenvironment play a critical role in maintaining hematopoiesis. [1][2][3][4][5] Hematopoietic growth factors are potent regulators of hematopoiesis. In addition, these proteins have been implicated in modulating adhesion between hematopoietic progenitor cells and extracellular matrix proteins via changes in integrin receptor activation. [6][7][8][9] The role of adhesion molecules alone or with growth factors in maintaining proliferation, differentiation, and survival of hematopoietic cells is less understood, 10,11 but collaboration between growth factor receptors and integrins has been hypothesized to be necessary for normal hematopoietic development. 12 Specifically, integrin receptors such as alpha 4 beta 1 (␣ 4 ␤ 1 ) and/or alpha 5 beta 1 (␣ 5 ␤ 1 ), may collaborate in unique ways with receptor tyrosine kinases, to influence cellular events. In this regard, mice deficient in the receptor tyrosine kinase, c-Kit, its ligand stem cell factor (SCF), or ␤ 1 integrins demonstrate hematopoietic defects of varying severity, suggesting critical roles for these proteins in normal blood development. 1,13,14 Our laboratory and other investigators have shown that receptors of the extracellular matrix protein, fibronectin (FN), are involved in the adhesion of hematopoietic cells, including stem and progenitor cells in the hematopoietic microenvironment. [15][16][17][18][19][20] FN is expressed at high levels throughout the hematopoietic microenvironment. 21,22 The FN molecule contains binding sites for heparin, collagen, fibrin, and gelatin, suggesting that it plays an important role in regulating the architecture of the hematopoietic microenvironment. The binding of hematopoietic cells to FN is mediated by at least 2 integrin receptors. The ␣ 5 ␤ 1 receptor recognizes the minimal binding sequence Arg-Gly-Asp (single-letter amino acid code: RGD), as well as 2 other synergistic binding sites, all of which are located within the cell-binding domain of the FN molecule, 23,24 and ␣ 4 ␤ 1 binds sequences within the alternatively spliced IIICS region of FN defined by the synthetic peptides CS-1 and CS-5. 25,26 These receptors play a critical role in normal hematopoietic development. 1,27,28 Mutant mice homozygous for null mutations of c-Kit, or its ligand SCF, die in embryonic development or shortly after birth due to severe anemia. 14,[29][30][31] Viable homozygous mutants of c-Kit also demonstrate severe anemia and a marked reduction in both immature and mature erythroid progenitors. Data from these mutant mice show a critical role for c-Kit-mediated signaling in normal erythroid development. 29,30 Interactions of erythroid cells with FN are also believed to be essential for erythropoiesis, particularly for terminal stages of erythroid differentiation. [32][33][34][35][36] Erythroid progenitors express both ␣ 4 ␤ 1 and ␣ 5 ␤ 1 . 37,38 Efficient production of mature cells in vitro requires adhesion to FN in some systems....

Functional characterization of human CD34+ cells that express low or high levels of the membrane antigen CD111 (nectin 1)

“…Differentiation towards the nonlymphoid lineages suggests that cytokine combinations that induce erythroid differentiation (and contain Epo) also induce a strong upregulation of CD111 expression on the cell surface. This is compatible with the high numbers of CFU-E that were detected while culturing CD34 + /CD111 bright cells in methyl-cellulose assays, and with the increased expression of CD49d and CD49e on CD34 + /CD111 bright cells, 49 as well as with the increased expression of CD11a on CD34 + /CD111 dim cells. 50 The kinetics of CD111 expression, compared with the kinetics of expression for other useful markers of the erythroid lineage (CD71, CD36 and glycophorin A) suggests that CD111 may be highly upregulated during the transition from the BFU-E stage, to the CFU-E stage; 50,51 during erythroid differentiation in vitro, CD111 expression appears to peak after approximately 1 week of culture, to decrease later.…”

Expression of the c-kit receptor characterizes a subset of neuroblastomas with favorable prognosis

“…Our observations nevertheless suggest that in vitro data do not necessarily reflect the situation in vivo. Indeed, c-kit may exert divergent functions depending on a modulation by milieu factors and differential interactions with intracellular effector pathways (Kapur et al, 2001), and alternative splicing of c-kit mRNA may elicit opposite effects (Caruana et al, 1999). Moreover, no comparative information concerning the biological behavior of neuroblasts with and without c-kit expression can be derived from these data (Cohen et al, 1994).…”

Apoptotic Death of Hematopoietic Tumor Cells through Potentiated and Sustained Adhesion to Fibronectin via VLA-4

“…In contrast, there have been also several reports demonstrating the negative effects of cell adhesion on cell survival. Integrinmediated adhesive interaction with FN was shown to cause apoptosis in myeloid cell lines (11,12) and erythroid progenitor cells (13). Although the molecular mechanisms underlying apoptosis were not defined, these studies clearly showed that integrin-mediated adhesion plays a negative role in the survival of hematopoietic progenitor/tumor cells.…”