CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation.
CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation.
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DOI：
10.1083/jcb.202012114
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发表时间：
2021-09-06
期刊：
影响因子：
--
通讯作者：
Machesky LM
中科院分区：
文献类型：
--
作者：
Le AH;Yelland T;Paul NR;Fort L;Nikolaou S;Ismail S;Machesky LM
Le等人暗示CYRI-A通过局部隔离活性RAC 1来解决巨胞饮体形成。他们进一步表明，CYRI介导的巨胞饮作用有助于整合素内化，影响癌细胞的扩散和侵袭。Scar/WAVE复合物在细胞迁移期间驱动肌动蛋白成核。有趣的是，相同的复合物在巨胞饮作用期间形成膜皱褶是重要的，巨胞饮作用是介导营养吸收和膜受体运输的过程。哺乳动物CYRI-B是最近描述的通过RAC 1隔离的瘢痕/WAVE复合物的负调节剂，但其另一种抑制剂CYRI-A尚未被表征。在这里，我们暗示CYRI-A作为巨胞饮体形成和整合素内化的关键调节因子。我们发现，CYRI-A是短暂招募新生的macropinosomes，依赖于PI 3 K和RAC 1活性。CYRI-A募集先于RAB 5A募集，但在RAC 1和肌动蛋白信号传导之后急剧跟随，这与它是肌动蛋白聚合的局部抑制剂一致。CYRI-A和-B两者的消耗通过减少的内化导致α5β1整联蛋白的表面表达增强。CYRI耗竭增强了3D中的迁移、侵袭和锚定非依赖性生长。因此，CYRI-A是巨胞饮作用的动态调节剂，与CYRI-B一起调节整联蛋白运输。
Le et al. implicate CYRI-A in resolving macropinosome formation by locally sequestering active RAC1. They further show that CYRI-mediated macropinocytosis contributes to integrin internalization, impacting spreading and invasion of cancer cells. The Scar/WAVE complex drives actin nucleation during cell migration. Interestingly, the same complex is important in forming membrane ruffles during macropinocytosis, a process mediating nutrient uptake and membrane receptor trafficking. Mammalian CYRI-B is a recently described negative regulator of the Scar/WAVE complex by RAC1 sequestration, but its other paralogue, CYRI-A, has not been characterized. Here, we implicate CYRI-A as a key regulator of macropinosome formation and integrin internalization. We find that CYRI-A is transiently recruited to nascent macropinosomes, dependent on PI3K and RAC1 activity. CYRI-A recruitment precedes RAB5A recruitment but follows sharply after RAC1 and actin signaling, consistent with it being a local inhibitor of actin polymerization. Depletion of both CYRI-A and -B results in enhanced surface expression of the α5β1 integrin via reduced internalization. CYRI depletion enhanced migration, invasion, and anchorage-independent growth in 3D. Thus, CYRI-A is a dynamic regulator of macropinocytosis, functioning together with CYRI-B to regulate integrin trafficking.
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影响因子：
21.3
作者：
Alanko J;Mai A;Jacquemet G;Schauer K;Kaukonen R;Saari M;Goud B;Ivaska J
通讯作者：
Ivaska J
影响因子：
14.8
作者：
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--
影响因子：
21.3
作者：
Fort L;Batista JM;Thomason PA;Spence HJ;Whitelaw JA;Tweedy L;Greaves J;Martin KJ;Anderson KI;Brown P;Lilla S;Neilson MP;Tafelmeyer P;Zanivan S;Ismail S;Bryant DM;Tomkinson NCO;Chamberlain LH;Mastick GS;Insall RH;Machesky LM
通讯作者：
Machesky LM
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
7.5
作者：
Carlsson AE
通讯作者：
Carlsson AE