PAK1 as a therapeutic target

Abstract

Importance of the field P21-activated kinases (PAKs) are involved in multiple signal transduction pathways in mammalian cells. PAKs, and PAK1 in particular, play a role in such disorders as cancer, mental retardation and allergy. Cell motility, survival and proliferation, the organization and function of cytoskeleton and extracellular matrix, transcription and translation are among the processes affected by PAK1. Areas covered in this review We discuss the mechanisms that control PAK1 activity; its involvement in physiological and pathophysiological processes; the benefits and the drawbacks of the current tools to regulate PAK1 activity; the evidences that point to PAK1 as a therapeutic target; and the likely directions of future research. What the reader will gain The reader will gain a better knowledge and understanding of the areas covered in this review. Take-home message PAK1 is a promising therapeutic target in cancer and allergen-induced disorders. Its suitability as a target in vascular, neurological and infectious diseases remains ambiguous. Further advancement of this field requires progress on such issues as the development of specific and clinically acceptable inhibitors, the choice between targeting one or multiple PAK isoforms, elucidation of the individual roles of PAK1 targets and the mechanisms that may circumvent inhibition of PAK1.

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

“…2 are a family of six serine-threonine kinases that are categorized into group I and group II Paks on the basis of their mechanism of activation (1). Group I Paks differ from their group II counterparts on their activation by small Rho GTPases such as Rac and cdc42 (2) as well as their specific involvement in inducing cytoskeletal changes and lamellipodia and filopodia formation in mammalian cells in the promotion of cell motility (1,3).…”

“…Group I Paks differ from their group II counterparts on their activation by small Rho GTPases such as Rac and cdc42 (2) as well as their specific involvement in inducing cytoskeletal changes and lamellipodia and filopodia formation in mammalian cells in the promotion of cell motility (1,3). Group II Paks lack the auto inhibitory domain, acidic and Pix-binding regions, as well as the cdc42/Rac interacting binding (CRIB) domain, which are present in all group I Pak isoforms (4 -6).…”

“…Among the Pak isoforms, group I Paks (Pak1 and Pak2 in particular) are the best characterized and most deregulated in cancers (1,3). We have shown previously that Pak1 is necessary for inducing cytoskeletal changes in normal cells (7) and in reconciling the effects of the Akt and ERK pathways, two major pathways deregulated in multiple cancers, thus mediating oncogenic transformation (8).…”

Immuno Expression of PAKs in Actinic Cheilitis and in Lip Squamous Cell Carcinoma

“…Their effects on the cytoskeleton can be dependent or independent of their kinase activity [24]. The PAKs proteins are involved in the formation of filopodia and lamelipodia, leading to cell motility [25]. Considering that this study was conducted only with lip carcinoma, which usually has a better prognosis, future studies may elucidate the involvement of the PAKs family in carcinogenesis of head and neck cancer.…”

The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer

“…В основе такой регуляции лежит фосфорилирование с участием РАК1 соответствующих сигнальных белков, в том числе: BAD (антиапоптотический сигналинг), RAF-1 (клеточное деление), LIM kinase (цитоскелет) и др. [7,8]. Примечательно, что в числе мишеней РАК оказался и рецептор эстрогенов: было установлено, что РАК-зависимое фосфорилирование ER приводит к эстрогеннезависимой активации последнего и способствует снижению гормональной зависимости ER-позитивных опухолей молочной железы [9][10][11].…”