The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB

EMBO J. 2001 Aug 15;20(16):4380-90. doi: 10.1093/emboj/20.16.4380.

Abstract

PKB/Akt, S6K1 and SGK are related protein kinases activated in a PI 3-kinase-dependent manner in response to insulin/growth factors signalling. Activation entails phosphorylation of these kinases at two residues, the T-loop and the hydrophobic motif. PDK1 activates S6K, SGK and PKB isoforms by phosphorylating these kinases at their T-loop. We demonstrate that a pocket in the kinase domain of PDK1, termed the 'PIF-binding pocket', plays a key role in mediating the interaction and phosphorylation of S6K1 and SGK1 at their T-loop motif by PDK1. Our data indicate that prior phosphorylation of S6K1 and SGK1 at their hydrophobic motif promotes their interaction with the PIF-binding pocket of PDK1 and their T-loop phosphorylation. Thus, the hydrophobic motif phosphorylation of S6K and SGK converts them into substrates that can be activated by PDK1. In contrast, the PIF-binding pocket of PDK1 is not required for the phosphorylation of PKBalpha by PDK1. The PIF-binding pocket represents a substrate recognition site on a protein kinase that is only required for the phosphorylation of a subset of its physiological substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Alanine / genetics
  • Alanine / metabolism
  • Alanine / physiology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Enzyme Activation
  • Glutamine / genetics
  • Glutamine / metabolism
  • Glutamine / physiology
  • Immediate-Early Proteins
  • Isoleucine / genetics
  • Isoleucine / metabolism
  • Isoleucine / physiology
  • Lysine / genetics
  • Lysine / metabolism
  • Lysine / physiology
  • Molecular Sequence Data
  • Nuclear Proteins*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases / metabolism*

Substances

  • Immediate-Early Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Isoleucine
  • Glutamine
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • serum-glucocorticoid regulated kinase
  • Lysine
  • Alanine