PAK family kinases come of age: Celebrating 40 years of discovery.

2018 Commentary to J. Cell Signal., accepted for publication (5/01/2018)

Hiroshi Maruta, PAK Research Center, Melbourne, Australia.

e-mail:  maruta20420@yahoo.co.jp

Introduction

Since our team at NIH found the very first member of PAK family kinases (called “myosin I heavy chain kinase”) in a soil amoeba in 1977 (1), this family of RAC/CDC42-dependent Ser/Thr kinases kept expanding their territory during the last four decades. Among this unique family, however, PAK1 has been most extensively studied so far, mainly because it is essential for malignant trans-formation of mammalian cells, but non-essential for normal cell growth (2), and shortens the healthy lifespan of small animals such as C. elegans (3), and is involved even in PDGF/a-MSH-dependent melanogenesis (4). For this reason, a variety of PAK1-blockers/inhibitors have been developed or identified since the turn of this century, and some of them such as propolis and 15K could be potentially useful for therapy of solid tumors, promoting the longevity by suppressing a variety of other PAK1-dependent diseases/disorders such as AD (Alzheimer’s disease), hyper-tension and diabetes (type 2), and even for the cosmetic treatment of hyper-pigmentation (so-called “skin-whitening”). Thus, the potential market value of these PAK1-blockers would be huge in both pharmaceutical and cosmetic industries. In this commentary, I shall briefly highlight the uniqueness of PAK1-blockers useful for signaling therapy causing no serious side effect, in contrast to conventional anti-cancer drugs such as DNA/RNA/microtubule poisons which clearly cause serious side effects such as hair-loss, suppression of immune system and loss of appetite. Rather surprisingly, these PAK1-blockers such as propolis and 15K promote hair growth and boost even our immune system (5, 6), easing the damaging side effects caused by conventional anti-cancer drugs.

References 

1. Maruta H, Korn ED. Acanthamoeba cofactor protein is a heavy chain kinase (PAK) required for actin activation of the Mg2+-ATPase activity of Acanthamoeba myosin I. J Biol Chem. 1977 ; 252: 8329-8332.
2. Maruta, H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res. 2014 ; 28: 656-672.
3. Yanase, S, Luo, Y, Maruta, H. PAK1-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in C. elegans. Drug Discov Ther. 2013; 7: 29-35.
4. Be-Tu PT, Nguyen BC, Tawata S, Yun CY, Kim EG, Maruta H. The serum/ PDGF-dependent “melanogenic” role of the minute level of the oncogenic kinase PAK1 in melanoma cells proven by the highly sensitive kinase assay, Drug Discov. Ther. 2016. 10:  314–322.
5. Nguyen BC, Taira N, Maruta H, Tawata S. Artepillin C and Other Herbal PAK1-blockers: Effects on Hair Cell Proliferation and Related PAK1-dependent Biological Function in Cell Culture. Phytother Res. 2016; 30: 120-127.
6. Huynh N, Wang K, Yim M, et al. Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis. BMC Cancer. 2017; 17: 431.