Prominin‐1 controls stem cell activation by orchestrating ciliary dynamics

Abstract

Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly–disassembly dynamics are under rigid cell cycle‐dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol‐binding membrane glycoprotein, Prominin‐1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.

Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3

“…The number of cells harboring no cilium was also increased upon expression of PROM1 Y819/828F mutants ( Fig. 1D) (33).…”

“…The latter observation might be associated with the implication of prom1 in cancer cell migration (32). The selective binding of prom1 to ADPribosylation factor-like protein 13B (Arl13b) or histone deacetylase 6 (HDAC6) can orchestrate the functionality and dynamics of primary cilia, and consequently the activation of stem cells (33). The interactions of Prom1 with Arl13b/HDAC6 appear to be dependent on cytoplasmic lysine 138 (numbered according to prom1 splice variant s2) (33,34), while binding to Arp2/3 complex is stimulated by phosphorylation of a Cterminal tyrosine residue located at position 819/828 (s1/s2 variant) (28,35).…”

“…The selective binding of prom1 to ADPribosylation factor-like protein 13B (Arl13b) or histone deacetylase 6 (HDAC6) can orchestrate the functionality and dynamics of primary cilia, and consequently the activation of stem cells (33). The interactions of Prom1 with Arl13b/HDAC6 appear to be dependent on cytoplasmic lysine 138 (numbered according to prom1 splice variant s2) (33,34), while binding to Arp2/3 complex is stimulated by phosphorylation of a Cterminal tyrosine residue located at position 819/828 (s1/s2 variant) (28,35). This posttranslational modification also promotes the interaction of prom1 with the p85 subunit of phosphoinositide 3-kinase (PI3K) thereby activating the transformation of phosphatidylinositol(4,5)-bisphosphate (PIP2) into phosphatidylinositol(3,4,5)trisphosphate (PIP3) at the inner leaflet of the plasma membrane (36), which plays a pivotal role in the organization of plasma membrane protrusions (28).…”

PROM1 and PROM2 expression differentially modulates clinical prognosis of cancer: a multiomics analysis

“…Prominins have been shown to contribute to the generation and development of various cancers [4,6,86]. PROM1 is reported to be a regulator of stem cell activation by modifying microvillar architecture and dynamics and ciliary dynamics [12,18]. PROM2 can cause cellular protrusions and enhance phosphorylation of caveolin-1 to promote endocytosis [23].…”

“…Moreover, PROM1 regulates metastasis, drug resistance, and stemness properties in various cancer cells [3,16,17]. It can also regulate the activation of stem cells by orchestrating ciliary dynamics, and the absence of PROM1 allows stem cells to resist the effects of sonic hedgehog (SHH) on growth stimulation, thereby disrupting stem cell activation [18]. Previous studies have shown that therapies targeting PROM1 may prevent tumor development in various human cancers [19][20][21][22].…”