TY - JOUR

T1 - The invariant chain CD74 protein is a cell surface binding partner of TIMP-1 in breast cancer cells

AU - Høeberg, Mikkel

AU - Noer, Julie Boertmann

AU - Vistesen, Mette Vixø

AU - Bartels, Annette

AU - Bech, Esben Matzen

AU - Nygård, Sune Boris

AU - Lademann, Ulrik

AU - Stenvang, Jan

AU - Liu, Siqi

AU - Fuglsang, Anja Thoe

AU - Brünner, Nils

AU - Moreira, José Manuel Afonso

N1 - Funding Information: We would like to thank all members of our research group for their expert assistance. This work was supported by the Sino‐Danish Center for Education and Research, Sawmill Owner Jeppe Juhl and wife Ovita Juhls Memorial Fund, and the Danish National Research Foundation (DNRF). Publisher Copyright: © 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2023

Y1 - 2023

N2 - Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates the proteolytic activity of matrix metalloproteinases (MMPs), playing an important role in the homeostasis of the extracellular matrix. Beyond its well-known role in tissue maintenance, TIMP-1 has been associated with multiple MMP-independent cytokine-like functions. The protein structure of TIMP-1, with two distinct domains, one interacting with MMPs and another able to bind multiple partners, provides a rationale for this multifunctionality. The identification of CD63 as a cell surface receptor for TIMP-1, able to mediate intracellular signaling through the Erk/MAPK axis, provided a molecular basis for the role of TIMP-1 in cellular signaling. However, several lines of evidence suggest that TIMP-1 may be able to associate with many interaction partners, thus attaining multiple functions. To enable the identification of previously unknown interaction partners that may underpin the core cellular functions of TIMP-1, known as well as unknown, we performed a yeast two-hybrid screening using a mammary gland complementary DNA (cDNA) library. We report here the identification of multiple interactors, including MHC class II-associated invariant chain γ (CD74). We verified that CD74 interacts with TIMP-1 in breast cancer cells and that this interaction contributes to cellular internalization of TIMP-1 and mediates intracellular signaling through the Akt signaling axis in breast cancer cells. These data provide new insights into the complex nature of the functions of TIMP-1 and their potential mechanistic basis.

AB - Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates the proteolytic activity of matrix metalloproteinases (MMPs), playing an important role in the homeostasis of the extracellular matrix. Beyond its well-known role in tissue maintenance, TIMP-1 has been associated with multiple MMP-independent cytokine-like functions. The protein structure of TIMP-1, with two distinct domains, one interacting with MMPs and another able to bind multiple partners, provides a rationale for this multifunctionality. The identification of CD63 as a cell surface receptor for TIMP-1, able to mediate intracellular signaling through the Erk/MAPK axis, provided a molecular basis for the role of TIMP-1 in cellular signaling. However, several lines of evidence suggest that TIMP-1 may be able to associate with many interaction partners, thus attaining multiple functions. To enable the identification of previously unknown interaction partners that may underpin the core cellular functions of TIMP-1, known as well as unknown, we performed a yeast two-hybrid screening using a mammary gland complementary DNA (cDNA) library. We report here the identification of multiple interactors, including MHC class II-associated invariant chain γ (CD74). We verified that CD74 interacts with TIMP-1 in breast cancer cells and that this interaction contributes to cellular internalization of TIMP-1 and mediates intracellular signaling through the Akt signaling axis in breast cancer cells. These data provide new insights into the complex nature of the functions of TIMP-1 and their potential mechanistic basis.

KW - breast cancer

KW - cell signaling

KW - invariant chain (CD74)

KW - receptor

KW - TIMP-1 interaction

U2 - 10.1002/1878-0261.13436

DO - 10.1002/1878-0261.13436

M3 - Journal article

C2 - 37081824

AN - SCOPUS:85157964644

VL - 17

SP - 1595

EP - 1612

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 8

ER -