がん細胞の移動の仕組みを解明し、標的治療への道を拓く(Understanding how cancer cells migrate paves the way for targeted therapies)

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2023-04-11 シンガポール国立大学(NUS)

がんは世界的に死因の主要な要因の1つであり、約6人に1人ががんで死亡しています。転移性がんは、がん関連死亡の90%以上を占めています。転移性がんは、がん細胞が体内の元の腫瘍から離れ、血管やリンパ系を通って他の臓器や組織に付着すると起こります。がん細胞が他の部位に広がる過程を研究し、がん治療の可能性のあるチェックポイントを発見するために科学者たちは努力しています。
シンガポールの国立大学の研究チームは、がん細胞が変化し、血管を通って移動する細胞活動を研究しました。BPGAP1という重要なタンパク質ががん細胞の移動を制御する役割を発見し、がん細胞の他の部位への広がりを防止するための標的がん治療の新しい機会を提供します。

<関連情報>

足場となるRhoGAPタンパク質ARHGAP8/BPGAP1は、RacとRhoシグナルを同期させ、細胞移動を促進する The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration

Darren Chen Pei Wong,Catherine Qiurong Pan,Shi Yin Er,T. Thivakar,Tan Zi Yi Rachel,Sock Hong Seah,Pei Jou Chua,Tingting Jiang,Ti Weng Chew,Parthiv Kant Chaudhuri,Somsubhro Mukherjee,Agus Salim,Thike Aye Aye,Cheng Gee Koh,Chwee Teck Lim,Puay Hoon Tan,Boon Huat Bay,Anne J. Ridley and Boon Chuan Low
Molecular Biology of the Cell  Published:1 Feb 2023
DOI:https://doi.org/10.1091/mbc.E21-03-0099

FIGURE 1:

Abstract

Rho GTPases regulate cell morphogenesis and motility under the tight control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the underlying mechanism(s) that coordinate their spatiotemporal activities, whether separately or together, remain unclear. We show that a prometastatic RhoGAP, ARHGAP8/BPGAP1, binds to inactive Rac1 and localizes to lamellipodia. BPGAP1 recruits the RacGEF Vav1 under epidermal growth factor (EGF) stimulation and activates Rac1, leading to polarized cell motility, spreading, invadopodium formation, and cell extravasation and promotes cancer cell migration. Importantly, BPGAP1 down-regulates local RhoA activity, which influences Rac1 binding to BPGAP1 and its subsequent activation by Vav1. Our results highlight the importance of BPGAP1 in recruiting Vav1 and Rac1 to promote Rac1 activation for cell motility. BPGAP1 also serves to control the timing of Rac1 activation with RhoA inactivation via its RhoGAP activity. BPGAP1, therefore, acts as a dual-function scaffold that recruits Vav1 to activate Rac1 while inactivating RhoA to synchronize both Rho and Rac signaling in cell motility. As epidermal growth factor receptor (EGFR), Vav1, RhoA, Rac1, and BPGAP1 are all associated with cancer metastasis, BPGAP1 could provide a crucial checkpoint for the EGFR-BPGAP1-Vav1-Rac1-RhoA signaling axis for cancer intervention.

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