PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6

Yanlin Yu; Meng Dai; Liping Huang; Weiping Chen; Ellen Yu; Arnulfo Mendoza; Helen Michael; Chand Khanna; Marcus Bosenberg; Martin McMahon; Glenn Merlino

doi:10.1016/j.isci.2023.106070

PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6

iScience. 2023 Jan 26;26(2):106070. doi: 10.1016/j.isci.2023.106070. eCollection 2023 Feb 17.

Authors

Yanlin Yu¹, Meng Dai², Liping Huang^{1

2}, Weiping Chen³, Ellen Yu¹, Arnulfo Mendoza⁴, Helen Michael¹, Chand Khanna⁴, Marcus Bosenberg⁵, Martin McMahon⁶, Glenn Merlino¹

Affiliations

¹ Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Southern Medical University, Guangzhou, People's Republic of China.
³ NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Yale University, New Haven, CT 06520, USA.
⁶ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Abstract

PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We demonstrate that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data indicate that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatment of PTEN mutant melanoma.

Keywords: Cancer; Cell biology; Functional aspects of cell biology.