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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging

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STAM and Hrs down-regulate ciliary TRP receptors.

Jinghua Hu¹, Samuel G Wittekind, Maureen M Barr

¹Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.

Molecular Biology of the Cell

|June 22, 2007

Summary

Signal transduction adaptor molecule STAM-1A and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) control polycystin localization in cilia. Their dysfunction leads to polycystin accumulation and sensory defects, revealing a novel regulatory mechanism for ciliary receptors.

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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

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Published on: November 11, 2016

Area of Science:

Cell Biology
Molecular Biology
Genetics

Background:

Cilia possess critical membrane receptors, channels, and signaling molecules requiring precise localization and function.
Polycystin-1 (PC1) and transient receptor polycystin-2 channel (TRPP2 or PC2) form a mechanosensory complex in mammalian kidney and C. elegans sensory cilia.
Mechanisms regulating polycystin activity, localization, and ciliary receptors are not well understood.

Purpose of the Study:

To investigate the regulatory mechanisms controlling the localization and function of ciliary polycystin complexes.
To identify proteins involved in the trafficking and degradation of ciliary receptors.
To elucidate the role of STAM and Hrs in regulating polycystin localization in sensory cilia.

Main Methods:

Interaction studies between STAM-1A and C. elegans LOV-1 (PC1).
Analysis of LOV-1 and PKD-2 localization in wild-type and stam-1 mutant C. elegans.
Assessment of sensory behavioral defects upon STAM or Hrs overexpression.

Main Results:

STAM-1A interacts with C. elegans LOV-1 (PC1).
STAM and Hrs function on early endosomes to target the LOV-1-PKD-2 complex for lysosomal degradation.
Loss of STAM function causes LOV-1 and PKD-2 to accumulate at the ciliary base.
Overexpression of STAM or Hrs leads to PKD-2 removal from cilia and sensory behavioral defects.

Conclusions:

The STAM-Hrs complex regulates the localization and signaling of the ciliary PC1-TRPP2 complex.
This complex plays a role in down-regulating ciliary receptors, similar to its function with cell surface receptors.
These findings provide new insights into the regulation of ciliary mechanosensory transduction and potential implications for polycystic kidney disease.