Oncogenic/Ageing Pathways Leading to the Activation of PAK1

Within cells, there are several distinct proteins essential for the full activation of the oncogenic/ ageing kinase PAK1. First of all, two distinct G proteins called RAC and CDC42 bind to the GBD domain of this kinase. This interaction leads to opening-up of this molecule.  Cucurbitacin, a triterpene from a bitter melon (Goya) in Okinawa, and CAPE (caffeic acid phenethyl ester) from propolis inactivates RAC, leading to the inactivation of PAK1.

Secondly, two SH3 adaptor proteins called PIX and NCR bind to the Pro-rich domains called "PAK18" and "PAK13" in the N-terminal half of this kinase. The PIX-PAK1 interaction requires phosphorylation of PAK1 at Tyr 285 by an oncogenic Tyr-kinase called JAK2. Cucurbitacin and Ursolic Acid (UA) from rosemary leaves directly inhibits JAK2 as well, thereby blocking the PIX-PAK1 interaction, leading to the inactivation of PAK1. In addition, the cell-permeable peptide "WR-PAK18" could block the PIX-PAK1 interaction, leading to the inactivation of PAK1.

Thirdly, its interaction with another Tyr-kinase called ETK is also required for the activation of PAK1. Thus, a synthetic compound called AG 879 that blocks the ETK-PAK1 interaction also inactivates PAK1. A third Tyr-kinase called FYN is also involved in the activation of PAK1. The anti-oncogenic kinase LKB1 is known to directly phosphorylate PAK1 at Thr 109 to inactivate PAK1, while phosphorylate another anti-oncogenic kinase called AMPK at Thr 172 to activate AMPK. FYN phosphorylates LKB1 for inactivation, leading to the activation of PAK1, and inactivation of AMPK. Thus, a synthetic FYN inhibitor called PP1/PP2 inactivates PAK1, while activating AMPK.

However, none of these PAK1-blocking compounds is available on the market for clinical application as yet. So far only a bee product(s) called "propolis" which blocks PAK1 through its anti-oncogenic ingredients including CAPE and ARC (artepillin C) is widely available as a health food/supplement for the treatment of cancers and other PAK1-dependent diseases/disorders since the ancient Egyptian era.

Continued