PDK1

Official Full Name

pyruvate dehydrogenase kinase 1

Organism

Homo sapiens

GeneID

5163

Background

Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2013]

Synonyms

PDK1; pyruvate dehydrogenase kinase, isozyme 1; pyruvate dehydrogenase kinase, isoenzyme 1; mitochondrial pyruvate dehydrogenase, lipoamide, kinase isoenzyme 1;

Bio Chemical Class

Kinase

Protein Sequence

MRLARLLRGAALAGPGPGLRAAGFSRSFSSDSGSSPASERGVPGQVDFYARFSPSPLSMKQFLDFGSVNACEKTSFMFLRQELPVRLANIMKEISLLPDNLLRTPSVQLVQSWYIQSLQELLDFKDKSAEDAKAIYDFTDTVIRIRNRHNDVIPTMAQGVIEYKESFGVDPVTSQNVQYFLDRFYMSRISIRMLLNQHSLLFGGKGKGSPSHRKHIGSINPNCNVLEVIKDGYENARRLCDLYYINSPELELEELNAKSPGQPIQVVYVPSHLYHMVFELFKNAMRATMEHHANRGVYPPIQVHVTLGNEDLTVKMSDRGGGVPLRKIDRLFNYMYSTAPRPRVETSRAVPLAGFGYGLPISRLYAQYFQGDLKLYSLEGYGTDAVIYIKALSTDSIERLPVYNKAAWKHYNTNHEADDWCVPSREPKDMTTFRSA

Open

Disease

Idiopathic interstitial pneumonitis, Inborn energy metabolism error, Insulin-resistance syndrome, Metastatic tumour, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

Introduction

The serine-threonine kinase PDK1 (or PDPK1) is a key element of signaling transduction activated by extracellular ligands, which recognized as a key regulator of cell migration and chemotaxis by controlling numerous elements of signaling transduction and cytoskeletal dynamics. PDK1 has been proved to exist in different cell types and organisms including endothelial cells, mammary epithelial cells, smooth muscle cells, T lymphocytes and neutrophils. Furthermore, PDK1 gene ablation or silencing is associated with tumor progression in different cellular and experimental models.

PDK1 and the Cell Migration

PDK1 (an ancient and conserved protein kinase) is found throughout the entire eukaryotic domain, whose importance in vertebrates is reflected in its relevant physiological roles in embryonic development and adulthood. PDK1 is a member of the AGC kinase family (cAMP-dependent, cGMP-dependent and protein kinase C), which includes 60 serine-threonine kinases with a common phylogenetic origin. PDK1 is responsible for the phosphorylation and activation of several other AGC kinases, such as p70S6K, SGK, p90RSK and atypical PKC isoforms, and is initially characterized for the phosphorylation of Akt on threonine 308 in the activation loop, which is essential for its activation. PDK1 is mainly localized in the cytoplasm and able to translocate into the nucleus with a mechanism that involves the inhibition of its nuclear export sequence. Previous studies have shown that PDK1 can move to the plasma membrane, which is essential for its ability to regulate cell migration.

PDK1 and the Signaling Pathways of Cell Migration

It is reported that the binding of PDK1 to plasma membrane phospholipid PtdIns (3, 4, 5) P3 produced by means of PI3K activity is one prominent explanation of the relevant role of PDK1 in regulating cell migration. PDK1 and Akt share the ability to bind PtdIns (3,4,5) P3 through their PH domains. When they colocalize at the plasma membrane, PDK1 phosphorylates Akt activation loop on threonine 308. PAK1 can bind the small GTPases cdc42 and RAC1, which event could potentially colocalize PDK1 and PAK1 at the plasma membrane at the leading edge. Moreover, PAK1 was shown involved in the regulation of cell migration through its substrates LIMK, p41-ARC, filamin A.

PDK1 Control Different Hallmarks of Tumor Invasion

Tumors may be defined as a wide group of somatic diseases accompanied by the uncontrolled proliferation of cells. The ability to invade surrounding tissues is considered a distinctive feature of malign ones. It has been reported that PDK1 plays a crucial role in different processes involved in tumor invasion and dissemination. PI3K/PDK1/Akt signaling axis is also required to form functional invadopodia with proteolytic activity as shown by in vitro gelatin degradation, but PDK1 and Akt inhibition provides an effective tool to block invadopodia formation which is sustained by the active and oncogenic forms of p110_α (E545K and H1047R). PDK1 is involved in the regulation of collective invasion in MCF10DCIS model of breast tumor by MRCK_αsignaling pathway, whose overexpression leads to the formation of multicellular invasive structures from MCF10DCIS spheroids in basement membrane gel.

Figure 1. PDK1 localizes at the leading edge of migrating cells by binding to PtdIns (3,4,5) P3 produced by PI3K. (http://dx.doi.org/10.1016/j.bbcan.2015.07.003)

References:

Paolo Armando Gagliardi, Laura di Blasio and Luca Primoa. (2015) 'PDK1: A signaling hub for cell migration and tumor invasion', Biochimica et Biophysica Acta, 1856: 178-188.
Paolo Armando Gagliardia, Alberto Puliafitoa and Luca Primo. (2018) 'PDK1: At the crossroad of cancer signaling pathways', Seminars in Cancer Biology, 48:27-35.
Pau Castel, Haley Ellis, Ruzica Bago, Eneda Toska, Pedram Razavi, F. Javier Carmona, Srinivasaraghavan Kannan, Chandra S. Verma, Maura Dickler, Sarat Chandarlapaty, Edi Brogi, Dario R. Alessi, Jose Baselga and Maurizio Scaltriti. (2016) 'PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Ka Inhibition', Cancer Cell, 30:229-242.

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