University of Oulu

Haapalainen, AM, Daddali, R, Hallman, M, Rämet, M. Human CPPED1 belongs to calcineurin-like metallophosphoesterase superfamily and dephosphorylates PI3K-AKT pathway component PAK4. J Cell Mol Med. 2021; 25: 6304– 6317.

Human CPPED1 belongs to calcineurin-like metallophosphoesterase superfamily and dephosphorylates PI3K-AKT pathway component PAK4

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Author: Haapalainen, Antti M.1,2; Daddali, Ravindra1,2; Hallman, Mikko1,2;
Organizations: 1PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland
2Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
3Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.1 MB)
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Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2021-09-01


Protein kinases and phosphatases regulate cellular processes by reversible phosphorylation and dephosphorylation events. CPPED1 is a recently identified serine/threonine protein phosphatase that dephosphorylates AKT1 of the PI3K-AKT signalling pathway. We previously showed that CPPED1 levels are down-regulated in the human placenta during spontaneous term birth. In this study, based on sequence comparisons, we propose that CPPED1 is a member of the class III phosphodiesterase (PDE) subfamily within the calcineurin-like metallophosphoesterase (MPE) superfamily rather than a member of the phosphoprotein phosphatase (PPP) or metal-dependent protein phosphatase (PPM) protein families. We used a human proteome microarray to identify 36 proteins that putatively interact with CPPED1. Of these, GRB2, PAK4 and PIK3R2 are known to regulate the PI3K-AKT pathway. We further confirmed CPPED1 interactions with PAK4 and PIK3R2 by coimmunoprecipitation analyses. We characterized the effect of CPPED1 on phosphorylation of PAK4 and PIK3R2 in vitro by mass spectrometry. CPPED1 dephosphorylated specific serine residues in PAK4, while phosphorylation levels in PIK3R2 remained unchanged. Our findings indicate that CPPED1 may regulate PI3K-AKT pathway activity at multiple levels. Higher CPPED1 levels may inhibit PI3K-AKT pathway maintaining pregnancy. Consequences of decreased CPPED1 expression during labour remain to be elucidated.

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Series: Journal of cellular and molecular medicine
ISSN: 1582-1838
ISSN-E: 1582-4934
ISSN-L: 1582-1838
Volume: 25
Issue: 13
Pages: 6304 - 6317
DOI: 10.1111/jcmm.16607
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Copyright information: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.