Molecular Pathways: Targeting P21-activated Kinase 1 Signaling in Cancer: Opportunities Challenges and Limitations

摘要

The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. The p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a plethora of its new functions in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely up-regulated in several human cancers including hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. The structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibilities to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize the PAK1 molecular pathways in human cancer and discuss the current status of PAK1 targeted anti-cancer therapies.