PDPK1

PDPK1 Background

The 3-phosphoinositide-dependent protein kinase 1 is a protein in humans that is encoded by PDPK1 gene. As a master kinase, PDPK1 phosphorylates and activates AKT1, among other proteins, and appears to play a role in signal transduction and development, maybe by mediating the activation of AKT1 by growth factors. PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate, and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is believed to be constitutively active and does not always require phosphatidylinositols for its activities. An important role for PDPK1 is in the signaling pathways activated by several growth factors and hormones including insulin signaling. Mice lacking PDPK1 die during early embryonic development, indicating that this enzyme is critical for transmitting the growth-promoting signals necessary for normal mammalian development. PDPK1-deficient mice have an about 40% decrease in body mass, mild glucose intolerance, and are resistant to cancer brought about by hyperactivation of the PI3K pathway (PTEN+/-) ^[1][2].

[1] Mora A, Komander D, van Aalten DM, Alessi DR (April 2004). "PDK1, the master regulator of AGC kinase signal transduction". Semin. Cell Dev. Biol. 15 (2): 161–70.
[2] Frödin M, Antal TL, Dümmler BA, Jensen CJ, Deak M, Gammeltoft S, Biondi RM (October 2002). "A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation". EMBO J. 21 (20): 5396–407.