Interaction of Hydroxylated Collagen IV with the von Hippel-Lindau Tumor Suppressor

Grosfeld, Alexandra; Stolze, Ineke; Cockman, Matthew E.; Pugh, Christopher W.; Edelmann, Mariola J.; Kessler, Benedikt M.; Bullock, Alex N.; Ratcliffe, Peter J.; Masson, Norma

doi:10.1074/jbc.m611648200

Cited by 61 publications

(48 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While we were preparing this manuscript, a study showing interaction of VHL with collagen IV was published (Grosfeld et al, 2007). We further confirm these results in our present study and move on to show the specificity of VHL to COL4A2, the ER localization of the VHL-COL4A2 interaction as well as the dependence of ECM assembly on this interaction.…”

Section: Discussionsupporting

confidence: 78%

Collagen matrix assembly is driven by the interaction of von Hippel–Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2

et al. 2007

View full text Add to dashboard Cite

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to vascular tumor formation in several organs. VHL regulates two evolutionary conserved pathways: the targeting of hydroxylated hypoxia-inducible factor-a (HIF-a) for proteasomal degradation and the remodeling of extracellular matrix (ECM). The biochemical mechanisms of the ECM assembly pathway remain poorly defined. Here, we provide evidence supporting a biochemical role for VHL in ECM assembly. We show that VHL directly binds to the collagen IV alpha 2 (COL4A2) chain and that this interaction is necessary for its assembly into the ECM. The VHL-COL4A2 interaction is dependent on endoplasmic reticulum (ER)-mediated COL4A2 hydroxylation and independent of cytosolic, hypoxia regulated HIF-a-modifying enzymes. We find that the N-terminal tail of COL4A2 protrudes from the ER lumen into the cytosol where it is bound by VHL. Failure of VHL to interact with COL4A2 correlates with loss of collagen IV network formation in vitro and collagen IV remodeling in vivo. Our data suggest a HIF-a-independent role for the VHL-COL4A2 interaction in suppression of angiogenic tumor formation through collagen IV network assembly.

show abstract

Section: Discussionsupporting

confidence: 78%

Collagen matrix assembly is driven by the interaction of von Hippel–Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2

et al. 2007

View full text Add to dashboard Cite

show abstract

“…However, this model appears to be inconsistent with the finding that HIF-2␣, its target gene product GLUT1, and JunB accumulate to very similar levels in VHL Ϫ/Ϫ renal cell carcinoma cell lines stably expressing type 1 and type 2B mutant proteins, respectively (27). Another HIF-independent function of pVHL that has been implicated in pheochromocytoma pathogenesis is its involvement in extracellular matrix assembly by virtue of interactions with fibronectin (25) and collagen IV (54,55). Again, however, type 1-and type 2-associated pVHL mutant proteins exhibit similar defects (25), making it unlikely that extracellular matrix assembly is critical with respect to pheochromocytoma.…”

Section: Discussioncontrasting

confidence: 40%

VHL Mutations Linked to Type 2C von Hippel-Lindau Disease Cause Extensive Structural Perturbations in pVHL

Knauth

Cartwright

Freund

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Similarly, pVHL interactions with various members of extracellular proteins are widely observed largely independent of HIF regulation. Such interactions include directed binding to hydroxylated collagen IV [56,57]. Evidence suggests additionally that pVHL operates along other pathways promoting extracellular matrix assembly.…”

Section: Vhl: Non-hif Activitiesmentioning

confidence: 99%

VHLinactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment

Rathmell¹,

Chen²

2008

Expert Review of Anticancer Therapy

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) provides a tumor paradigm for the integration of genetics, molecular biology, therapeutic target validation, and the introduction of high impact treatment strategies. Most cases of sporadic as well as familial ccRCC acquire somatic inactivating mutations of the von Hippel-Lindau tumor suppressor gene, VHL. pVHL, VHL gene product and a protein member of the E3 ubiquitin ligase family, acts in normal cells to direct the degradation and clearance of the hypoxia inducible factor (HIFα) transcription factor family, such that in its absence, as in ccRCC, the HIF proteins stabilize, accumulate to supraphysiologic levels, and activate the transcription of genes such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), which contributes substantially to the physiology of the tumor, and has been assessed indirectly as a prognostic factor. Molecularly targeted therapy blocking components of this pathway has been successfully introduced to the clinic with a substantive impact on clinical parameters of RCC. This review will examine the regulation of these molecular pathways in RCC and discuss the impact on the clinical management of patients with RCC.

show abstract

Interaction of Hydroxylated Collagen IV with the von Hippel-Lindau Tumor Suppressor

Cited by 61 publications

References 26 publications

Collagen matrix assembly is driven by the interaction of von Hippel–Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2

Collagen matrix assembly is driven by the interaction of von Hippel–Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2

VHL Mutations Linked to Type 2C von Hippel-Lindau Disease Cause Extensive Structural Perturbations in pVHL

VHLinactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment

Contact Info

Product

Resources

About