MicroRNA Regulation of Kinase Activity

It is known that Rho-associated kinase (ROCK) signaling plays a fundamental role in regulating cell morphology, adhesion, and motility and that aberrant expression of ROCK is related to tumor metastases and poor clinical outcome. Researchers at Tufts University proposed that ROCK may enhance the metastatic propensity of breast cancer cells by promoting the c-Myc pathway, including transcription of c-Myc–regulated miRNAs (miR-17-92 cluster)1. They used microRNA microarray analysis to show a 2- to 6-fold increase in expression of the miR-17-92 cluster in two metastatic breast cancer cell lines compared with non metastatic cells. Additionally, they showed that an anti-miR can block the ROCK signaling pathway resulting in decreased breast cancer cell invasion/ migration and metastasis. Therefore, inhibition of ROCK-mediated signaling appears to be a promising and potentially specific approach to suppress breast cancer metastases.

Numerous miRNAs have been shown to act as positive and negative regulators of the phosphoinositide-3-kinase (PI3K)/Akt-signaling pathway. The miR-29 family and miR-126 negatively affect the pathway through repression of PI3K regulatory subunits and many miRNAs positively influence PI3K/Akt signaling by targeting phosphatase and tensin homolog (PTEN) for inhibition which negatively affect phosphoinositide-3-kinase (PI3K)/Akt signaling. Researchers at the University of Texas Southwestern Medical Center, Dallas performed microarray analysis and found that miR-486 showed a dramatic increase in expression in myocardin-related transcription factor-A (MRTF-A)–transduced cells2. PTEN is a strongly predicted target of miR-486 and they further demonstrated that inhibition of miR-486 expression enhances the expression of PTEN and dampens signaling through the PI3K/Akt-signaling pathway.  These findings implicate miR- 486 as another potential modulator of PI3K/Akt signaling.

  1. Liu S, Goldstein RH, Scepansky EM, Rosenblatt M.  (2009) Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human boneCancer Res 69(22), 8742-51. [abstract]
  2. Small EM, O’Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, Richardson JA, Olson EN. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci U S A 107(9), 4218-23. [abstract]

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