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
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
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DOI：
10.1182/blood.v97.7.1975
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发表时间：
2001-04-01
期刊：
影响因子：
20.3
通讯作者：
Williams, DA
中科院分区：
文献类型：
--
作者：
Kapur, R;Cooper, R;Williams, DA
在缺乏配体干细胞因子（SCF）、其受体c-Kit或β(1)-整合素的小鼠中，红细胞祖细胞（EPCs）是缺乏的。在非造血细胞中，整合素和受体酪氨酸激酶可以协同调节细胞功能，为这些细胞表面分子产生的信号之间的串扰提供了证据。本研究使用含有整合素α (4) β (1) （FN-H296）或α (5) β (1) （FN-CH271）或α (4) β(1)和α (5) β (1) （FN-CH296）结合位点的特异性重组纤维连接蛋白肽，研究了粘附单独或联合c-Kit激活对EPC细胞系、G1E-ER2和原代EPCs的功能和生化结果的影响。与在FN-H296或FN-CH296上生长的细胞相比，在c-KR激活的情况下，在FN-CH271上培养的G1E-ER2细胞和原代EPCs的增殖显著增加，在FN-H296或FN-CH296上培养的G1E-ER2细胞与在FN-CH271上生长的细胞相比，在FN-H296或FN-CH296上培养的细胞显著死亡，c-Kit的激活提高了在FN-H296或FN-CH296上生长的G1E-ER2细胞的存活率；然而，救援只是局部的。FN-H296上G1E-ER2细胞的存活减少与Akt的激活以及Bcl-2和Bcl-x的表达减少(L)相关，而FN-CH271上增殖增加与局灶黏附激酶（FAK）和细胞外调节激酶（ERK）途径的显著增强和持续激活相关。这些数据表明，由α (4) β(1)和α (5) β(1)结扎产生的粘附诱导信号导致不同的生物学结果，包括通过α (4) β(1)死亡和通过α (5) β(1)存活/增殖（Blood, 2001;97:1975-1981） (C) 2001，美国血液学会。
Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or beta (1)-integrins, In nonhematopoietic cells, integrins and receptor tyrosine kinases can collaborate to modulate cellular functions, providing evidence for cross-talk between signals emerging from these cell surface molecules. Using specific recombinant fibronectin peptides that contain the binding site for the integrin alpha (4)beta (1) (FN-H296) or alpha (5)beta (1) (FN-CH271) Or both alpha (4)beta (1) and alpha (5)beta (1) (FN-CH296), this study investigated the effect of adhesion alone, or in combination with activation of c-Kit, on functional and biochemical outcomes in an EPC line, G1E-ER2, and primary EPCs, G1E-ER2 cells and primary EPCs cultured on FN-CH271 in the presence of c-KR activation led to a significant increase in proliferation in comparison with cells grown on FN-H296 or FN-CH296, G1E-ER2 cells cultured on FN-H296 or FN-CH296 resulted in significant cell death in comparison to cells grown on FN-CH271, Activation of c-Kit enhanced the survival of G1E-ER2 cells grown on FN-H296 or FN-CH296; however, the rescue was only partial. The reduced survival of G1E-ER2 cells on FN-H296 correlated with reduced activation of Akt and expression of Bcl-2 and Bcl-x(L), whereas increase in proliferation on FN-CH271 correlated with significantly enhanced and sustained activation of focal adhesion kinase (FAK) and extracellular-regulated kinase (ERK) pathways. These data demonstrate that adhesion-induced signals emanating from ligation of alpha (4)beta (1) and alpha (5)beta (1) result in distinct biologic outcomes, including death via alpha (4)beta (1) and survival/proliferation via alpha (5)beta (1) (Blood, 2001;97:1975-1981) (C) 2001 by The American Society of Hematology.