期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 7, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2019.00269
关键词
mechanotransduction; invasion; PAK; integrin beta-3; invadopodia
资金
- National Institutes of Health Center grant [P30 CA022453]
- Perinatology Research Branch of the National Institutes of Child Health and Development at the Wayne State University
Cancer cells are affected by a wide range of mechanical forces within their extracellular environment. It has been widely shown that these forces can lead to increased metastatic activity of these cells. One such force is a transient tugging-like force that results from contractile forces generated by cells within the tumor microenvironment. When this force is simulated in vitro with a mechano-invasion assay, human fibrosarcoma cells exhibit enhanced cell invasion in a 3D collagen-fibronectin matrix by downregulating the expression of integrin beta 3. Furthermore, this force stimulates the maturation of invadopodia in an integrin beta 3-dependent manner that includes an increase in the active form of cofilin and MMP-2 secretion. In the present study we discovered that the decrease in integrin beta 3 signaling in response to mechanical stimulation is coupled to the activity of p21-activated kinase 1 (PAK1). It was found that PAK1 has decreased activity, as detected by a decrease in Ser144 phosphorylation, with mechanical stimulation. However, this loss in phosphorylation can be reversed if integrin beta 3 is overexpressed. Furthermore, PAK1 mutants show a correlated response in MMP-2 enzyme expression and activity, in addition to the lengthening of invadopodia, in response to stimulation. These results identify a novel mechano-sensitive response in human fibrosarcoma that utilizes PAK1 as a signaling player positioned downstream of integrin beta 3.
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