Pterostilbene in Blueberry: A natural PAK1 blocker that directly inhibits the Tyr-kinase JAK2

Blueberry is known to be rich in pterostilbene (PTE), which is di-methoxyl derivative of resveratrol (R3). The bioavailability of PTE is much higher than that of R3. Interestingly, this year, a Chinese group found that PTE directly inhibits the Tyr-kinase JAK2, and the growth of a bone cancer called osteosarcoma (1). Nearly two decades ago (around 1996), Alex Levitzki’s group at Hebrew University in Israel developed a synthetic chemical called AG 490, which also directly inhibits JAK2. Interestingly, the over-all chemical structure of AG 490 is quite similar to PTE. 

How does PTE or AG 490 blocks the growth of osteosarcoma?  Back to 2007, Maria Diakonova’s group at University of Toledo, Ohio, found that JAK2 activates PAK1 by phosphorylating three Tyr residues at 153, 201, and 285 (2). In other words, like many other solid tumors such as pancreatic, colon and breast cancers as well as NF (neurofibromatosis), osteosarcoma is among PAK1-dependent cancers, and natural PAK1-blocking products such as Blueberry and Propolis extracts would be useful for the effective therapy of these solid tumors.

Furthermore, an aging disease called AD (Alzheimer’s disease) also depends on PAK1, and PTE is reported to improve the AD conditions in a mouse model. 

Moreover, our recent study showed that PAK1 shortens the lifespan of C. elegans (3), suggesting the possibility that natural PAK1-blockers (such as blueberry and propolis) could extend our healthy lifespan. Indeed blueberry was shown to extend lifespan of C. elegans (4). 

 

Does prolactin, that activates JAK2 (2), mediate RAS-induced PAK1 activation?   YES, more than 2 decades ago,  a group at University of Colorado in Denver showed that RAS activates prolactin gene (5), and thereby JAK2 as well. Thus, at least three distinct Tyr-kinases (ETK, FYN and JAK2) are involved in RAS-induced PAK1 activation.

 

References:

1. Liu Y, Wang L, Wu Y, Lv C, Li X, Cao X, Yang M, Feng D, Luo Z. Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway. Toxicology. 2013 Jan 8.
2. Rider L, Shatrova A, Feener EP, Webb L, Diakonova M. JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions. J Biol Chem. 2007; 282:30985-96.
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 Dev Ther. 2013, in press. 
4. Wilson MA, Shukitt-Hale B, Kalt W, Ingram DK, Joseph JA, Wolkow CA.  Blueberry polyphenols increase lifespan and thermotolerance in C. elegans. Aging Cell. 2006 ;5:59-68.
5.  Conrad KE, Gutierrez-Hartmann A. The RAS and PKA pathways are mutually antagonistic in regulating rat prolactin promoter activity. Oncogene. 1992, 7:1279-86.