TY - JOUR
T1 - MACC1 regulates clathrin-mediated endocytosis and receptor recycling of transferrin receptor and EGFR in colorectal cancer
AU - Imbastari, Francesca
AU - Dahlmann, Mathias
AU - Sporbert, Anje
AU - Mattioli, Camilla Ciolli
AU - Mari, Tommaso
AU - Scholz, Florian
AU - Timm, Lena
AU - Twamley, Shailey
AU - Migotti, Rebekka
AU - Walther, Wolfgang
AU - Dittmar, Gunnar
AU - Rehm, Armin
AU - Stein, Ulrike
N1 - Funding Information:
Open Access funding enabled and organized by Projekt DEAL. The project was supported by the Helmholtz-graduate school of the Max-Delbrück-Center for Molecular Medicine, Berlin (to FI), and by the German Cancer Consortium (DKTK), Heidelberg (to US, MD, WW).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/4
Y1 - 2021/4
N2 - Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis. By exploring the MACC1 interactome, we identified the clathrin-mediated endocytosis (CME)-associated proteins CLTC, DNM2 and AP-2 as MACC1 binding partners. We unveiled a MACC1-dependent routing of internalized transferrin receptor towards recycling. Elevated MACC1 expression caused also the activation and internalization of EGFR, a higher rate of receptor recycling, as well as earlier and stronger receptor activation and downstream signaling. These effects are limited by deletion of CME-related protein interaction sites in MACC1. Thus, MACC1 regulates CME and receptor recycling, causing increased growth factor-mediated downstream signaling and cell proliferation. This novel mechanism unveils potential therapeutic intervention points restricting MACC1-driven metastasis.
AB - Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis. By exploring the MACC1 interactome, we identified the clathrin-mediated endocytosis (CME)-associated proteins CLTC, DNM2 and AP-2 as MACC1 binding partners. We unveiled a MACC1-dependent routing of internalized transferrin receptor towards recycling. Elevated MACC1 expression caused also the activation and internalization of EGFR, a higher rate of receptor recycling, as well as earlier and stronger receptor activation and downstream signaling. These effects are limited by deletion of CME-related protein interaction sites in MACC1. Thus, MACC1 regulates CME and receptor recycling, causing increased growth factor-mediated downstream signaling and cell proliferation. This novel mechanism unveils potential therapeutic intervention points restricting MACC1-driven metastasis.
KW - CME
KW - Colorectal cancer
KW - EGFR
KW - MACC1
KW - Receptor recycling
KW - Transferrin receptor
UR - http://www.scopus.com/inward/record.url?scp=85099572658&partnerID=8YFLogxK
U2 - 10.1007/s00018-020-03734-1
DO - 10.1007/s00018-020-03734-1
M3 - Article
C2 - 33469705
AN - SCOPUS:85099572658
SN - 1420-682X
VL - 78
SP - 3525
EP - 3542
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 7
ER -