FLNa is a ubiquitous cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and functions as a signalling intermediate. We investigated FLNa's role in the function of integrin-type collagen receptors, EGF-EGFR signalling and regulation of PKB/Akt and ERK1/2. Using FLNa-deficient M2 human melanoma cells, and same cells expressing EGFP-FLNa (M2F) or its Ig-like repeats 1-8+24, 8-15+24 and 16-24, we found that in M2F and M2 8-15+24 cells, EGF induced the increased phosphorylation of PKB/Akt and ERK1/2. In M2F cells EGF induced the localisation of these kinases to cell nucleus and lamellipodia, respectively, and the ERK1/2 phosphorylation-dependent co-immunoprecipitation of FLNa with ERK1/2. Only M2F and M2 8-15+24 cells adhered to and spread on type I collagen whereas on fibronectin all cells behaved similarly. α1β1 and α2β1 were the integrin-type collagen receptors expressed on these cells with primarily α1β1 localising to focal contacts and affecting cell adhesion and migration in a manner dependent on FLNa or its Ig-like repeats 8-15. Our results suggest a role for FLNa repeats 8-15 in the α1-subunit-dependent regulation of integrin α1β1 function, EGF-EGFR signalling to PKB/Akt and ERK1/2, identify ERK1/2 in EGF-induced FLNa-associated protein complexes, and show that the function of different integrins is subjected to differential regulation by FLNa.

中文翻译：

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人黑色素瘤细胞中FLNa的表达调节整联蛋白α1β1的功能以及PKB / AKT / ERK1 / 2激酶的磷酸化和定位。

FLNa是一种普遍存在的细胞骨架蛋白，可将包括整合素在内的跨膜受体与F-肌动蛋白连接，并起信号传导中间体的作用。我们调查了FLNa在整合素型胶原受体功能，EGF-EGFR信号传导以及对PKB / Akt和ERK1 / 2的调节中的作用。使用缺乏FLNa的M2人黑素瘤细胞，以及表达EGFP-FLNa（M2F）或其Ig样重复序列1-8 + 24、8-15 + 24和16-24的相同细胞，我们发现在M2F和M2 8-在15 + 24个细胞中，EGF诱导PKB / Akt和ERK1 / 2的磷酸化增加。在M2F细胞中，EGF分别诱导这些激酶定位于细胞核和层状脂膜，并诱导FLNa与ERK1 / 2的ERK1 / 2磷酸化依赖性免疫共沉淀。只有M2F和M2 8-15 + 24细胞粘附并扩散在I型胶原上，而在纤连蛋白上，所有细胞的行为都相似。α1β1和α2β1是在这些细胞上表达的整联蛋白型胶原蛋白受体，α1β1主要位于局部接触并以依赖于FLNa或其Ig样重复序列8-15的方式影响细胞粘附和迁移。我们的结果表明，FLNa重复序列8-15在整合素α1β1功能，α1亚基依赖性调节，EGF-EGFR信号转导至PKB / Akt和ERK1 / 2的过程中发挥作用，在EGF诱导的FLNa相关蛋白复合物中鉴定ERK1 / 2。 ，并表明不同整合素的功能受到FLNa的差异调节。