Abstract
Regulation of Shp2, a tyrosine phosphatase, critically influences the development of various diseases. Its role in epithelial lumenogenesis is not clear. Here we show that oncogenic Shp2 dephosphorylates Tuba to decrease Cdc42 activation, leading to the abnormal multi-lumen formation of epithelial cells. HDAC6 suppression reverses oncogenic Shp2-induced multiple apical domains and spindle mis-orientation during division in cysts to acquire normal lumenogenesis. Intriguingly, Cdc42 activity is not restored in this rescued process. We present evidence that simultaneous reduction in myosin II and ERK1/2 activity by HDAC6 inhibition is responsible for the reversion. In HER2-positive breast cancer cells, Shp2 also mediates Cdc42 repression, and HDAC6 inhibition or co-suppression of ERK/myosin II promotes normal epithelial lumen phenotype without increasing Cdc42 activity. Our data suggest a mechanism of epithelial disorganization by Shp2 deregulation, and reveal the cellular context where HDAC6 suppression is capable of establishing normal epithelial lumenogenesis independent of Cdc42.
Highlights
Regulation of Shp[2], a tyrosine phosphatase, critically influences the development of various diseases
A recent report has demonstrated that microtubule acetylation by HDAC6 inhibition decreases myosin II activity by promoting myosin phosphatase binding to myosin light chain (MLC)[36] In agreement, we found that HDAC6 inhibition causes a concurrent reduction in ERK and myosin II activity
To know the effect of oncogenic Shp2-E76G in epithelial organization, we embedded these cells in Matrigel for 3 days
Summary
Regulation of Shp[2], a tyrosine phosphatase, critically influences the development of various diseases. In HER2-positive breast cancer cells, Shp[2] mediates Cdc[42] repression, and HDAC6 inhibition or co-suppression of ERK/myosin II promotes normal epithelial lumen phenotype without increasing Cdc[42] activity. Knockdown of Shp[2] in MCF10A-HER2/3 cells or BT474 cells is sufficient to rescue hollow lumen phenotypes in three-dimensional (3D) culture[20,21,22] It remains elusive how oncogenic Shp[2] acts to cause epithelial disorganization. We found that HDAC6 suppression restores normal epithelial lumen formation in MDCK cells expressing oncogenic Shp[2] cells This reversion is independent of Cdc[42] signal or aPKC activity. The suppression of HDAC6 allows the apical–basal polarity formation in a context deficient of Cdc42-mediated signal through attenuating ERK and myosin II
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