Les fleurs du PTEN

Les fleurs du Mal is a volume of poetry by Baudelaire about the beauty of evil and depravity. I have the same esthetic appreciation for the horrible things a mutant of PTEN does. It’s awful, but incredibly elegant chemically.

Back in the day med students used to be told ‘know syphylis and you’ll know medicine’ because of its varied clinical manifestations. PTEN is like that for cellular and molecular biology.

PTEN (Phosphatase and TENsin homolog) is a gene mutated in many forms of cancer. So it was regarded as a tumor suppressor, keeping our cells on the straight and narrow. Naturally cancer cells ‘try’ (note the anthropomorphism) to neutralize it. PI3K is a universal tumor driver, integrating growth factor signaling with downstream circuitries of cell proliferation, metabolism and survival.

Inositol is a 6 membered ring (all carbons) with one OH group attached to each carbon, which are numbered 1 through 6. PI3K puts phosphate on the 3 position, PTEN takes it off. Since this is how PI3K signaling begins, cells lacking PTEN grow faster and migrate aberrantly (e.g. spread).

Enter Proc. Natl. Acad. Sci. vol. 112 pp. 13976 – 13981 ’15 which carefully studied a PTEN mutant found in an unfortunate man with aggressive prostate cancer. It just changed one of the 403 amino acids (#126) from alanine to glycine. Not a big deal you say,it’s just a change of CH3 (alanine) to H (glycine). #126 is near the active site of the enzyme. One might expect that the mutation inhibits PTEN’s phosphatase activity (e.g. its enzymatic activity). Not so — the mutations shifts the activity so the enzyme. Instead of removing phosphate from the 3 position of inositol, the phosphate at the 5 position is removed (leaving the 3 position alone). This shifts inositol phosphate levels in the cell with hyperactivation of PI3K signaling (which requires inositol phospholipids containing phosphate at the 3 position).

What happens is that inositol phosphates fit into the mutant active site with the 5 position near the catalytic amino acid (cysteine). Essentially the 6 membered ring rotates the 3 position away from cysteine and puts the 5 position there instead. This changes PTEN from a tumor suppressor (anti-oncogene) to an oncogene.

To a chemist this is elegant and beautiful (apologies Baudelaire).

PTEN has taught us a huge amount about the control of protein levels, pseudogenes, competitive endogenous RNA (ceRNA). You can read all about this in https://luysii.wordpress.com/2014/01/20/why-drug-discovery-is-so-hard-reason-24-is-the-3-untranslated-region-of-every-protein-a-cerna/

That’s fairly grim, so here’s a link to one of the great comedians of years past — Jonathan Winters

http://biggeekdad.com/2013/04/jonathan-winters-stick/

It’s politically incorrect and sure to offend the humorless pompous prigs. Enjoy ! ! !

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Comments

  • hopeforheather  On December 8, 2015 at 5:08 pm

    I have a PTEN mutation. I wish I understood better your post. 🙂

  • luysii  On December 8, 2015 at 10:35 pm

    I wish we understood PTEN better. If we did, then we’d know better how to help you

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