CD98hc (SLC3A2) mediates integrin signaling
CD98hc (SLC3A2) mediates integrin signaling
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DOI：
10.1073/pnas.0404852102
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发表时间：
2005-01-11
影响因子：
11.1
通讯作者：
Ginsberg, MH
中科院分区：
文献类型：
--
作者：
Feral, CC;Nishiya, N;Ginsberg, MH
整合素通过包括Rho gtp酶和激酶在内的信号通路调节细胞行为。CD98异源二聚体由一条重链（CD98hc, SLC3A2）和一条轻链组成，通过CD98hc与整合素相互作用。CD98hc过表达导致3T3成纤维细胞不依赖于锚定的细胞生长和肿瘤发生，并激活某些整合素调节的信号通路。为了确定CD98hc的生物学功能，我们破坏了该基因并分析了CD98hc缺失的细胞。在这里，我们报道CD98hc有助于整合素依赖的细胞扩散、细胞迁移和保护细胞免于凋亡。此外，CD98hc是有效的粘附诱导Akt和Rac GTPase激活所必需的，Akt和Rac GTPase是参与细胞存活和细胞迁移的整合素依赖信号的主要来源。CD98通过其轻链促进氨基酸运输；然而，CD98hc突变体与β 1整合素相互作用，而不与CD98轻链相互作用，恢复了整合素依赖的信号传导并保护细胞免于凋亡。β 1整合素参与了某些癌症的发病机制。CD98hc缺失显著损害小鼠胚胎干细胞形成畸胎癌的能力；通过CD98hc或只与整合素相互作用的突变体的重新表达，畸胎癌的形成得以重建。因此，CD98hc是一种整合素相关蛋白，介导整合素依赖信号，促进肿瘤发生。
Integrins regulate cellular behaviors through signaling pathways, including Rho GTPases and kinases. CD98 heterodimers, comprised of a heavy chain (CD98hc, SLC3A2) and one of several light chains, interact with integrins through CD98hc. CD98hc overexpression leads to anchorage-independent cell growth and tumorigenesis in 3T3 fibroblasts and activates certain integrin-regulated signaling pathways. To establish the biological function of CD98hc, we disrupted the gene and analyzed CD98hc-null cells. Here we report that CD98hc contributes to integrin-dependent cell spreading, cell migration, and protection from apoptosis. Furthermore, CD98hc is required for efficient adhesion-induced activation of Akt and Rac GTPase, major contributors to the integrin-dependent signals involved in cell survival and cell migration. CD98 promotes amino acid transport through its light chains; however, a CD98hc mutant that interacts with beta1 integrins, but not CD98 light chains, restored integrin-dependent signaling and protection from apoptosis. beta1 integrins are involved in the pathogenesis of certain cancers. CD98hc deletion markedly impaired the ability of embryonic stem cells to form teratocarcinomas in mice; teratocarcinoma formation was reconstituted by reexpression of CD98hc or of the mutant that interacts exclusively with integrins. Thus, CD98hc is an integrin-associated protein that mediates integrin-dependent signals, which promote tumorigenesis.