Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.

Autor:	Zutshi N; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Mohapatra BC; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA., Mondal P; Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA., An W; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Goetz BT; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Wang S; Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA., Li S; Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA., Storck MD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Mercer DF; Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA., Black AR; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Thayer SP; Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Black JD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Lin C; Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Band V; Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Band H; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 May 08; Vol. 27 (6), pp. 109912. Date of Electronic Publication: 2024 May 08 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.109912
Abstrakt:	Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl -knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro , Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation. Competing Interests: H.B. and V.B. received funding from Nimbus Therapeutics for an unrelated project. (© 2024 The Author(s).)
Databáze:	MEDLINE
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