Q9Z2A0

FUNCTION: Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF- kappa-B activation in macrophages. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-376 and Tyr-379 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-244 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-376 and Tyr-379 by INSR in response to insulin (By similarity). SUBUNIT: Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PAK1, PTK2B, GRB14, STRAP and IKKB. The Tyr- 9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-244 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ (By similarity). Interacts with PKN1 (via C-terminus) and PPARG. SUBCELLULAR LOCATION: Cytoplasm. Nucleus (By similarity). Cell membrane; Peripheral membrane protein. Cell junction, focal adhesion (By similarity). Note=Tyrosine phosphorylation seems to occur only at the cell membrane. Translocates to the cell membrane following insulin stimulation by a mechanism that involves binding to GRB14 and INSR. SRC and HSP90 promote its localization to the cell membrane. Its nuclear localization is dependent on its association with PTPN6 and its phosphorylation at Ser-396. Restricted to the nucleus in neuronal cells while in non-neuronal cells it is found in the cytoplasm. The Ser-244 phosphorylated form is distributed along the perinuclear region in neuronal cellls while in non-neuronal cells it is found in both the nucleus and the cytoplasm. IGF1 transiently increases phosphorylation at Ser-241 of neuronal PDPK1, resulting in its translocation to other cellular compartments. The tyrosine-phosphorylated form colocalizes with PTK2B in focal adhesions after angiotensin II stimulation (By similarity). TISSUE SPECIFICITY: Highly expressed in heart, brain, liver and testis, also expressed in embryonic cells. DOMAIN: The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization (By similarity). PTM: Phosphorylation on Ser-244 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-244, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-376 and Tyr-379 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-244 and palmitate-induced phosphorylation at Ser-532 and Ser-504 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-357 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-397 and Ser-401 by MAP3K5 (By similarity). PTM: Monoubiquitinated in the kinase domain, deubiquitinated by USP4 (By similarity). DISRUPTION PHENOTYPE: Mice show severe pancreatic hypoplasia at birth and ensuing hyperglycemia at postnatal stages and die of heart failure by 11 weeks of age. SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily. SIMILARITY: Contains 1 PH domain. SIMILARITY: Contains 1 protein kinase domain. GENE SYNONYMS:Pdpk1 Pdk1. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License., SEQUENCE 559 AA; 63759 MW; F2A617A27460FAC9 CRC64;

PDPK1_MOUSE

urn:biopax:ModificationFeature:PDPK1_MOUSE_1, urn:biopax:ModificationFeature:PDPK1_MOUSE_10, urn:biopax:ModificationFeature:PDPK1_MOUSE_11, urn:biopax:ModificationFeature:PDPK1_MOUSE_12, urn:biopax:ModificationFeature:PDPK1_MOUSE_13, urn:biopax:ModificationFeature:PDPK1_MOUSE_14, urn:biopax:ModificationFeature:PDPK1_MOUSE_15, urn:biopax:ModificationFeature:PDPK1_MOUSE_16, urn:biopax:ModificationFeature:PDPK1_MOUSE_17, urn:biopax:ModificationFeature:PDPK1_MOUSE_2, urn:biopax:ModificationFeature:PDPK1_MOUSE_3, urn:biopax:ModificationFeature:PDPK1_MOUSE_4, urn:biopax:ModificationFeature:PDPK1_MOUSE_5, urn:biopax:ModificationFeature:PDPK1_MOUSE_6, urn:biopax:ModificationFeature:PDPK1_MOUSE_7, urn:biopax:ModificationFeature:PDPK1_MOUSE_8, urn:biopax:ModificationFeature:PDPK1_MOUSE_9

MARTTSQLYDAVPIQSSVVLCSCPSPSMVRSQTEPGSSPGIPSGVSRQGSTMDGTTAEARPSTNPLQQHPAQLPPQPRKKRPEDFKFGKILGEGSFSTVVLARELATSREYAIKILEKRHIIKENKVPYVTRERDVMSRLDHPFFVKLYFTFQDDEKLYFGLSYAKNGELLKYIRKIGSFDETCTRFYTAEIVSALEYLHGKGIIHRDLKPENILLNEDMHIQITDFGTAKVLSPESKQARANSFVGTAQYVSPELLTEKSACKSSDLWALGCIIYQLVAGLPPFRAGNEYLIFQKIIKLEYHFPEKFFPKARDLVEKLLVLDATKRLGCEEMEGYGPLKAHPFFETITWENLHQQTPPKLTAYLPAMSEDDEDCYGNYDNLLSQFGFMQVSSSSSSHSLSTVETSLPQRSGSNIEQYIHDLDTNSFELDLQFSEDEKRLLLEKQAGGNPWHQFVENNLILKMGPVDKRKGLFARRRQLLLTEGPHLYYVDPVNKVLKGEIPWSQELRPEAKNFKTFFVHTPNRTYYLMDPSGNAHKWCRKIQEVWRQQYQSNPDAAVQ