Abstract
The lamellipodium, an essential structure for cell migration, plays an important role in the invasion and metastasis of cancer cells. Although Rac1 recognized as a key player in the formation of lamellipodia, the molecular mechanisms underlying lamellipodial motility are not fully understood. Optogenetic technology enabled us to spatiotemporally control the activity of photoactivatable Rac1 (PA-Rac1) in living cells. Using this system, we revealed the role of phosphatidylinositol 3-kinase (PI3K) in Rac1-dependent lamellipodial motility in PC-3 prostate cancer cells. Through local blue laser irradiation of PA-Rac1-expressing cells, lamellipodial motility was reversibly induced. First, outward extension of a lamellipodium parallel to the substratum was observed. The extended lamellipodium then showed ruffling activity at the periphery. Notably, PI(3,4,5)P3 and WAVE2 were localized in the extending lamellipodium in a PI3K-dependent manner. We confirmed that the inhibition of PI3K activity greatly suppressed lamellipodial extension, while the ruffling activity was less affected. These results suggest that Rac1-induced lamellipodial motility consists of two distinct activities, PI3K-dependent outward extension and PI3K-independent ruffling.
Highlights
Cell migration plays an important role in embryonic organogenesis; wound healing and immune responses; and the pathogenesis of several diseases including cancer invasion and metastasis [1,2]
After 1–4 min of irradiation with the 445 nm laser, a thin sheet-like protrusion extending parallel to the substratum was observed at the cell peripheral site that was irradiated by the 445 nm laser
We clearly showed that PI(3,4,5)P3 and the Rac1 downstream effector protein WAVE2 act in a coordinated manner in lamellipodial extension, which contributes to the migration of prostate cancer cells
Summary
Cell migration plays an important role in embryonic organogenesis; wound healing and immune responses; and the pathogenesis of several diseases including cancer invasion and metastasis [1,2]. An understanding of the molecular mechanisms underlying cell migration is important for developing new therapeutic strategies for preventing tumor invasion and metastasis. During the tumor cell migration that is associated with cancer metastasis and invasion, metastatic cells exhibit drastic changes in shape. This deformation is caused by actin cytoskeletal remodeling, which is regulated by Rho family GTPases such as Cdc and Rac. The inhibition of Rac activity blocks the migration and invasion of prostate cancer cells [5]. These studies suggest that Rac1-mediated lamellipodial formation plays an important role in prostate cancer metastasis
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