PAK2

What is PAK2 protein?

PAK2 (p21 (RAC1) activated kinase 2) gene is a protein coding gene which situated on the long arm of chromosome 3 at locus 3q29. Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene. The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The PAK2 protein is consisted of 524 amino acids and its molecular mass is approximately 58 kDa.

What is the function of PAK2 protein?

Full-length PAK2 stimulates cell survival and cell growth. It phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. PAK2 phosphorylates many other substrates including histone H4 and JUN. Additionally, it associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway.

Fig1. Proposed working model for the differential activation of PAK2 by Cdc42 and caspase 3. (John Huang, 2020)

PAK2 Related Signaling Pathway

The RAC1 signaling pathway is an important signaling pathway involved in a variety of cellular functions and biological processes. PAK2 phosphorylation activates RAC1, thereby regulating cell morphology, migration, proliferation and other physiological processes. In addition, PAK2 can also interact with other signaling pathways, such as Wnt/β-catenin signaling pathway, ERK/MAPK signaling pathway, TGF-β signaling pathway, etc.

PAK2 Related Diseases

PAK2 is abnormally expressed in a variety of cancers, including breast, lung, colon, and stomach cancers. Mutations in the PAK2 gene can lead to the onset and development of brain aneurysms or heart valve disease. At the same time, PAK2 deficiency can lead to abnormal function of the immune system, resulting in susceptibility to infection, and then the development of immunodeficiency syndrome.

Bioapplications of PAK2

The study of the PAK2 protein has enabled drug developers to develop novel drugs for diseases such as cancer and neurodegenerative diseases. These drugs can regulate the relevant signaling pathways by inhibiting or activating the action of the PAK2 protein, thereby enabling the treatment and prevention of the disease.

Case study 1: Lisbeth L V Møller, 2020

Muscle contraction is an important alternative pathway to increase glucose transport in insulin-resistant states, but the intracellular signaling mechanisms are not fully understood. PAK1 and PAK2 could be downstream effectors of Rac1 in contraction-stimulated glucose transport. The current study aimed to test the hypothesis that PAK1 and/or PAK2 regulate contraction-induced glucose transport.

Glucose transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA-3) of group I PAKs or originating from whole-body PAK1 knockout, muscle-specific PAK2 knockout or double whole-body PAK1 and muscle-specific PAK2 knockout mice. Lack of PAK2, either alone (-13%) or in combination with PAK1 (-14%), partly reduced contraction-stimulated glucose transport compared to control littermates in EDL, but not soleus muscle. Contraction-stimulated glucose transport in isolated glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1.

Fig1. Representative blots showing PAK1 and PAK2 protein expression in soleus (a) and extensor digitorum longus (EDL; b) muscles from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO, PAK1/2 double KO (1/m2 dKO) mice, or control littermates.

Fig2. Canonical contraction signaling is largely unaffected by the lack of PAK1 and PAK2.

Case study 2: John Huang, 2020

Cdc42-activated PAK2 mediates cytostasis, whereas caspase 3-cleaved PAK2 contributes to apoptosis. However, the relationship between these two states of PAK2 activation remains elusive. In this study, through protein biochemical analyses and various cell-based assays, the researchers demonstrated that full-length PAK2 activated by Cdc42 was resistant to the cleavage by caspase 3 in vitro and within cells.

This study identified two states of PAK2 activation, wherein Cdc42- and autophosphorylation-dependent activation inhibited the constitutive activation of PAK2 by caspase cleavage. The regulation between these two states of PAK2 activation provides a new molecular mechanism to support PAK2 as a molecular switch for controlling cytostasis and apoptosis in response to different types and levels of stress with broad physiological and pathological relevance.

Fig3. HEK 293T cells were co-transfected with HA-tagged wild type or mutant forms of PAK2 and Cdc42-L61 (active) or Cdc42-N17 (inactive) as indicated.

Fig4. HEK 293T cells were transfected with HA-PAK2/pcDNA 3.1+ constructs encoding WT and K278R mutant PAK2.

PAK2 has several biochemical functions, for example, ATP binding,Rac GTPase binding,identical protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PAK2 itself. We selected most functions PAK2 had, and list some proteins which have the same functions with PAK2. You can find most of the proteins on our site.

PAK2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PAK2 here. Most of them are supplied by our site. Hope this information will be useful for your research of PAK2.

RAC1;SORBS3;CDC42;N/A;ARHGEF7