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Publication : Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis.

First Author  Stewart BZ Year  2023
Journal  Proc Natl Acad Sci U S A Volume  120
Issue  23 Pages  e2220851120
PubMed ID  37252981 Mgi Jnum  J:343091
Mgi Id  MGI:7563836 Doi  10.1073/pnas.2220851120
Citation  Stewart BZ, et al. (2023) Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis. Proc Natl Acad Sci U S A 120(23):e2220851120
abstractText  G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 muM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D(3) levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.
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