RIPK1 binds to vitamin D receptor and decreases vitamin D-induced growth suppression

Waise Quarni1, Panida Lungchukiet1, Anfernee Tse1

  • 1The Departments of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL 33612, United States.

Insights

Receptor interacting protein kinase 1 (RIPK1) negatively regulates vitamin D signaling by inhibiting the vitamin D receptor (VDR). Depleting RIPK1 enhances vitamin D

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Receptor interacting protein kinase 1 (RIPK1) is implicated in cell survival and death pathways.
  • RIPK1 is known to confer drug resistance in cancer cells.
  • The role of RIPK1 in vitamin D signaling remains unexplored.

Purpose of the Study:

  • To investigate the role of RIPK1 in 1,25-dihydroxyvitamin D3 (1,25D3)-induced growth suppression.
  • To determine if RIPK1 modulates the activity of the vitamin D receptor (VDR).

Main Methods:

  • Luciferase reporter assays to assess VDR transcriptional activity.
  • Co-immunoprecipitation to detect RIPK1-VDR complex formation.
  • Subcellular fractionation to analyze VDR localization.
  • Experiments using RIPK1-null MEFs and RIPK1-knockdown cancer cells.

Main Results:

  • RIPK1 inhibited VDR transcriptional activity independently of its kinase activity.
  • RIPK1 directly binds to the VDR ligand-binding domain.
  • RIPK1 promotes VDR retention in the cytoplasm, reducing its transcriptional function.
  • 1,25D3-induced growth suppression was enhanced in RIPK1-deficient cells.

Conclusions:

  • RIPK1 acts as a repressor of VDR.
  • RIPK1 depletion potentiates 1,25D3-mediated growth suppression.
  • Targeting RIPK1 could enhance vitamin D-based cancer therapies.

Related Concept Videos

Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
20.2K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.0K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.9K
Role of Skin in Vitamin D Synthesis01:23

Role of Skin in Vitamin D Synthesis

The skin plays a crucial role in the synthesis of vitamin D, a vital nutrient for various physiological processes in the body. Vitamin D is unique because it can be synthesized in the skin through a series of chemical reactions triggered by exposure to ultraviolet B (UVB) radiation from sunlight.
The solar UV B rays (290-315 nm) are absorbed by the skin, and 7-dehydrocholesterol (provitamin D3) photolyzes it to previtamin D3, which undergoes a rapid transformation to vitamin...
8.5K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.0K