The Very First Book on PAKs (Elsevier "Insight" Series) in 2013:

“PAKs, RAC/CDC42(p21)-activated Kinases:　

Towards the Cure of Cancer and Other PAK-dependent Diseases”

edited by Hiroshi Maruta (NF/TSC Cure Org., Melbourne, Australia)

Contents:

Introduction (Hiroshi Maruta)

Pushing the Boundary toward Clinic: 35-Year PAK Research Comes of Age

  

Chapter 1:  “Functional Maturation of PAKs:  from Uni-cellular to Multi-cellular   

                     Organisms”

                      (Masato Okada, Graham Cote, Ramesh Jha, Hiroshi Maruta),

                      Osaka University, Japan

Chapter 2:  “Oncogenicity of PAKs and Their Substrates”

                    (Hong He & Hiroshi Maruta) University of Melbourne, Australia

Chapter 3:  “Natural or Synthetic Therapeutics that Block PAKs”

                    (Hiroshi Maruta, Shanta Messerli, Ramesh Jha)

                    NF/TSC Cure Org,  Melbourne, Australia

Chapter 4:  “PAK1-3 in Infectious Diseases (Malaria, AIDS, flu, etc) ”

                    ( Hiroshi Maruta) NF/TSC Cure Org,  Melbourne, Australia

Chapter 5:  “PAK1 in Brain Diseases” (NF, TSC, glioma, RB, epilepsy, depression, LD) 

                    (Hiroshi Maruta & Shanta Messerli) Marine Biological Lab, USA

Chapter 6:  ”PAK1 in Alzheimer’s and Huntington’s diseases”

                    (Qiu-Lan Ma, Fusheng Yang, Sally Frautschy and Greg Cole)

                    UCLA, USA

Chapter 7:  “PAK1 Controls the Lifespan”

                    (Sumino Yanase & Hiroshi Maruta) Daito Bunka University, Japan

Chapter 8:  “3D Structure and Physiological Regulation of PAKs ”

                  （Stefan Knapp）Oxford University, UK

Epilogue (Hiroshi Maruta)

Lateral Thinking is the Key for a Great Leap of Bio-medical Sciences.

PAK is a family of Ser/Thr kinases which are activated by RAS-related G proteins of 21 kDa (p21) called RAC and CDC42. Although the first mammalian PAKs (PAK1 and PAK2) were cloned by Ed Manser’s group in Singapore around 1994 (1), the first member of PAK family was isolated by our team at NIH in a soil amoeba as Acanthamoeba myosin I heavy chain kinase (MIHCK) in 1977 (2), far before a series of small G proteins (p21) such as RAS and RAC/CDC42 were discovered during 1980s. The myosin I is a small unconventional “single-headed” myosin which unlike the conventional double-headed myosins (myosin II) lacks the C-terminal tail, and requires the phosphorylation of its heavy chain by the MIHCK for actin-activation of its intrinsic ATPase activity (2).  Once myosin I is phosphorylated, its interaction with actin-filament (F-actin) triggered a rapid ATP hydrolysis and actomyosin complex (microfilament) associated with leading edge of amoeba contracts, and so-called amoeboid movement or membrane ruffling occurs...

 Shortly after the oncogenic RAS-RAC/CDC42-PAKs signaling pathway was about to be established in mid-1990s, Jeff Field’s group in Philadelphia discovered that RAS indeed activates PAK1, and over-expression of the dominant negative (DN) mutant of PAK1 in both RAS-transformed fibroblasts and NF1-deficient MPNST (malignant peripheral nerve sheath  tumor), in which RAS is abnormally activated, can reverse their malignant phenotype both in vitro and in vivo (4, 5), strongly suggesting that PAK1 is essential for the RAS-induced malignant transformation (anchorage-independent growth) of cells... 

Rather surprisingly, several non-tumor diseases such as AIDS, malaria, flu, Alzheimer’s (AD), Huntington’s (HD), inflammatory diseases such as asthma and arthritis, hyper-tension, epilepsy, depression, schizophrenia and autism associated with fragile X syndrome (FXS) also turned out to be PAK1-dependent. Thus, the potential market value of these PAK1 blockers would be huge in the future...

Afraxis in San Diego, founded by Susumu Tonegawa of MIT (the 1987 Nobel laureate) and his colleagues, recently developed a potent PAK1-specific inhibitor called "FRAX597" (IC₅₀ around 10 nM), which  passes the blood brain barrier. So they can test its effect on the long term memory in mice, and if this PAK1-specific inhibitor can cure or delay a variety of the known PAK1-dependent brain diseases/disorders such as NF (neurofibromatosis) and TSC (tuberous sclerosis).

Celebrating such an exciting PAK1-specific inhibitor development, in the above 8 chapters, world experts in his or her own specific fields would discuss in detail with their deep insight, how PAKs, in particular the oncogenic kinases PAK1 and PAK4 or their blockers, could control our life and health in a variety of aspects, and how mammalian PAKs are functionally being evolved from their ancestral origin(s) in uni-cellular organisms such as yeast and amoeba with a series of mutations over million years.