scholarly journals The von Hippel–Lindau tumour-suppressor protein interaction with protein kinase Cδ

2006 ◽  
Vol 397 (1) ◽  
pp. 109-120 ◽  
Author(s):  
Xavier Iturrioz ◽  
Joanne Durgan ◽  
Véronique Calleja ◽  
Banafshé Larijani ◽  
Heiwa Okuda ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ubiquitin Ligase ◽  
Catalytic Domain ◽  
Interaction Analysis ◽  
Resonance Energy ◽  
Tumour Suppressor ◽  
Fluorescence Lifetime Imaging ◽  
Α Subunit ◽  
Von Hippel Lindau ◽  
Tumour Suppressor Protein

The VHL (von Hippel–Lindau) tumour-suppressor protein forms a multi-protein complex [VCB (pVHL–elongin C–elongin B)–Cul-2 (Cullin-2)] with elongin C, elongin B, Cul-2 and Rbx1, acting as a ubiquitin-ligase (E3) and directing proteasome-dependent degradation of targeted proteins. The α-subunit of Hif1α (hypoxia-inducible factor 1α) is the principal substrate for the VCB–Cul-2 complex; however, other substrates such as aPKC (atypical protein kinase C) have been reported. In the present study, we show with FRET (fluorescence resonance energy transfer) analysis measured by FLIM (fluorescence lifetime imaging microscopy) that PKCδ and pVHL (VHL protein) interact directly in cells. This occurs through the catalytic domain of PKCδ (residues 432–508), which appears to interact with two regions of pVHL, residues 113–122 and 130–154. Despite this robust interaction, analysis of the PMA-induced proteasome-dependent degradation of PKCδ in different RCC (renal cell carcinoma) lines (RCC4, UMRC2 and 786 O) shows that there is no correlation between the degradation of PKCδ and the presence of active pVHL. Thus, in contrast with aPKC, PKCδ is not a conventional substrate of the ubiquitin-ligase complex, VCB–Cul-2, and the observed interaction between these two proteins must underlie a distinct signalling output.

scholarly journals Functions of the von Hippel–Lindau tumour suppressor protein

1998 ◽  
Vol 243 (6) ◽  
pp. 535-539 ◽  
Author(s):  
Kaelin ◽  
Iliopoulos ◽  
Lonergan ◽  
Ohh
Keyword(s):  
Tumour Suppressor ◽  
Von Hippel Lindau ◽  
Tumour Suppressor Protein

The multifaceted von Hippel-Lindau tumour suppressor protein

FEBS Letters ◽  
2014 ◽  
Vol 588 (16) ◽  
pp. 2704-2711 ◽  
Author(s):  
Claire M. Robinson ◽  
Michael Ohh
Keyword(s):  
Tumour Suppressor ◽  
Von Hippel Lindau ◽  
Tumour Suppressor Protein

Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL

2002 ◽  
Vol 5 (1) ◽  
pp. 64-70 ◽  
Author(s):  
Alexander Hergovich ◽  
Joanna Lisztwan ◽  
Robert Barry ◽  
Pia Ballschmieter ◽  
Wilhelm Krek
Keyword(s):  
Tumour Suppressor ◽  
Von Hippel Lindau ◽  
Microtubule Stability ◽  
Tumour Suppressor Protein

scholarly journals Hypoxia-inducible factors in the kidney

2006 ◽  
Vol 291 (2) ◽  
pp. F271-F281 ◽  
Author(s):  
Volker H. Haase
Keyword(s):  
Ubiquitin Ligase ◽  
Cell Types ◽  
Biological Processes ◽  
Hypoxia Inducible Factors ◽  
Α Subunit ◽  
Von Hippel Lindau ◽  
Helix Loop Helix ◽  
Pathological Conditions ◽  
Expression Of Genes ◽  
Oxygen Sensitive

Tissue hypoxia not only occurs under pathological conditions but is also an important microenvironmental factor that is critical for normal embryonic development. Hypoxia-inducible factors HIF-1 and HIF-2 are oxygen-sensitive basic helix-loop-helix transcription factors, which regulate biological processes that facilitate both oxygen delivery and cellular adaptation to oxygen deprivation. HIFs consist of an oxygen-sensitive α-subunit, HIF-α, and a constitutively expressed β-subunit, HIF-β, and regulate the expression of genes that are involved in energy metabolism, angiogenesis, erythropoiesis and iron metabolism, cell proliferation, apoptosis, and other biological processes. Under conditions of normal Po2, HIF-α is hydroxylated and targeted for rapid proteasomal degradation by the von Hippel-Lindau (VHL) E3-ubiquitin ligase. When cells experience hypoxia, HIF-α is stabilized and either dimerizes with HIF-β in the nucleus to form transcriptionally active HIF, executing the canonical hypoxia response, or it physically interacts with unrelated proteins, thereby enabling convergence of HIF oxygen sensing with other signaling pathways. In the normal, fully developed kidney, HIF-1α is expressed in most cell types, whereas HIF-2α is mainly found in renal interstitial fibroblast-like cells and endothelial cells. This review summarizes some of the most recent advances in the HIF field and discusses their relevance to renal development, normal kidney function and disease.

scholarly journals The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation

2006 ◽  
Vol 394 (3) ◽  
pp. 545-555 ◽  
Author(s):  
Mahaboobi Jaleel ◽  
Fabrizio Villa ◽  
Maria Deak ◽  
Rachel Toth ◽  
Alan R. Prescott ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Catalytic Domain ◽  
Limited Proteolysis ◽  
Cancer Syndrome ◽  
Tumour Suppressor Protein ◽  
Kinase Catalytic Domain ◽  
Uba Domain ◽  
Significant Conformational Change ◽  
Amp Activated Protein Kinase

Recent work indicates that the LKB1 tumour suppressor protein kinase, which is mutated in Peutz–Jeghers cancer syndrome, phosphorylates and activates a group of protein kinases that are related to AMPK (AMP-activated protein kinase). Ten of the 14 AMPK-related protein kinases activated by LKB1, including SIK (salt-induced kinase), MARK (microtubule-affinity-regulating kinase) and BRSK (brain-specific kinase) isoforms, possess a ubiquitin-associated (UBA) domain immediately C-terminal to the kinase catalytic domain. These are the only protein kinases in the human genome known to possess a UBA domain, but their roles in regulating AMPK-related kinases are unknown. We have investigated the roles that the UBA domain may play in regulating these enzymes. Limited proteolysis of MARK2 revealed that the kinase and UBA domains were contained within a fragment that was resistant to trypsin proteolysis. SAXS (small-angle X-ray scattering) analysis of inactive and active LKB1-phosphorylated MARK2 revealed that activation of MARK2 is accompanied by a significant conformational change that alters the orientation of the UBA domain with respect to the catalytic domain. Our results indicate that none of the UBA domains found in AMPK-related kinases interact with polyubiquitin or other ubiquitin-like molecules. Instead, the UBA domains appear to play an essential conformational role and are required for the LKB1-mediated phosphorylation and activation of AMPK-related kinases. This is based on the findings that mutation or removal of the UBA domains of several AMPK-related kinases, including isoforms of MARK, SIK and BRSK, markedly impaired the catalytic activity and LKB1-mediated phosphorylation of these enzymes. We also provide evidence that the UBA domains do not function as LKB1–STRAD (STE20-related adaptor)–MO25 (mouse protein 25) docking/interacting sites and that mutations in the UBA domain of SIK suppressed the ability of SIK to localize within punctate regions of the nucleus. Taken together, these findings suggest that the UBA domains of AMPK-related kinases play an important role in regulating the conformation, activation and localization of these enzymes.

Mobility of the von Hippel–Lindau tumour suppressor protein is regulated by kinesin-2

2008 ◽  
Vol 314 (6) ◽  
pp. 1229-1236 ◽  
Author(s):  
Dorus A. Mans ◽  
Martijn P. Lolkema ◽  
Moniek van Beest ◽  
Laura G. Daenen ◽  
Emile E. Voest ◽  
...  
Keyword(s):  
Tumour Suppressor ◽  
Von Hippel Lindau ◽  
Tumour Suppressor Protein

scholarly journals Kinase-independent transcriptional co-activation of peroxisome proliferator-activated receptor α by AMP-activated protein kinase

2004 ◽  
Vol 384 (2) ◽  
pp. 295-305 ◽  
Author(s):  
Myriam BRONNER ◽  
Rachel HERTZ ◽  
Jacob BAR-TANA
Keyword(s):  
Protein Kinase ◽  
Kinase Activity ◽  
Catalytic Domain ◽  
Phosphorylation Site ◽  
Atp Depletion ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Α Subunit ◽  
Co Activation ◽  
Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) responds to intracellular ATP depletion, while PPARα (peroxisome proliferator-activated receptor α) induces the expression of genes coding for enzymes and proteins involved in increasing cellular ATP yields. PPARα-mediated transcription is shown here to be co-activated by the α subunit of AMPK, as well as by kinase-deficient (Thr172Ala) and kinase-less (Asp157Ala, Asp139Ala) mutants of AMPKα. The Ser452Ala mutant of mPPARα mutated in its putative consensus AMPKα phosphorylation site is similarly co-activated by AMPKα. AMPKα or its kinase-less mutants bind to PPARα; binding is increased by MgATP, to a lesser extent by MgADP, but not at all by AMP or ZMP [AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) monophosphate]. ATP-activated binding of AMPKα to PPARα is mediated primarily by the C-terminal regulatory domain of AMPKα. PPARα co-activation by AMPKα may, however, require its secondary interaction with the N-terminal catalytic domain of AMPKα, independently of its kinase activity. While AMPK catalytic activity is activated by AICAR, PPARα co-activation and PPARα-controlled transcription are robustly inhibited by AICAR, with concomitant translocation of nuclear AMPKα or its kinase-less mutants to the cytosol. In conclusion, AMPKα, independently of its kinase activity, co-activates PPARα both in primary rat hepatocytes and in PPARα-transfected cells. The kinase and transcriptional co-activation modes of AMPKα are both regulated by the cellular ATP/AMP ratio. Co-activation of PPARα by AMPKα may transcriptionally complement AMPK in maintaining cellular ATP status.

scholarly journals Degradation of hDlg and MAGIs by human papillomavirus E6 is E6-AP-independent

2004 ◽  
Vol 85 (10) ◽  
pp. 2815-2819 ◽  
Author(s):  
Helena Sterlinko Grm ◽  
Lawrence Banks
Keyword(s):  
Ubiquitin Ligase ◽  
Human Papillomaviruses ◽  
Tumour Suppressor ◽  
Cellular Proteins ◽  
Dependent Manner ◽  
Compelling Evidence ◽  
Tumour Suppressor Protein ◽  
Discs Large

An important characteristic of the E6 proteins derived from cancer-associated human papillomaviruses (HPVs) is their ability to target cellular proteins for ubiquitin-mediated degradation. Degradation of the p53 tumour suppressor protein by E6 is known to involve the cellular ubiquitin ligase, E6-AP; however, it is presently not known how E6 targets the Drosophila discs large (Dlg) tumour suppressor and the membrane-associated guanylate kinase inverted (MAGI) family of proteins for degradation. By using an in vitro E6-AP immunodepletion assay, these targets were tested for degradation in a E6-AP-dependent manner. The data showed clearly that E6 can direct the degradation of Dlg and the MAGI family of proteins in the absence of E6-AP in this in vitro system. These results provide compelling evidence for the role of E6-associated ubiquitin ligases other than E6-AP in the degradation of certain E6 targets.

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