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| Item Type: | Article |
|---|---|
| Title: | MACC1 hyperactivates receptor tyrosine kinase signaling through phosphorylation-dependent adaptor activity in colorectal cancer cells |
| Creators: |
Zincke, Fabian, Kobelt, Dennis  ORCID: https://orcid.org/0000-0002-9373-0648, Kläger, Susan, Pachl, Fiona, Erdmann, Gerrit ORCID: https://orcid.org/0000-0002-4183-3995, Dahlmann, Mathias ORCID: https://orcid.org/0000-0002-0036-5283, Walther, Wolfgang ORCID: https://orcid.org/0000-0003-2360-1370, Küster, Bernhard ORCID: https://orcid.org/0000-0002-9094-1677 and Stein, Ulrike ORCID: https://orcid.org/0000-0001-7006-282X
|
| Abstract: | Understanding the mechanisms of metastasis is one of the most pressing issues in cancer therapy. Metastasis-associated in colon cancer 1 (MACC1) is an important biomarker and functional driver of tumor progression and metastasis. However, the molecular mechanisms underlying its activity remain incompletely understood. Here, we demonstrate that MACC1 acts as an important adaptor protein that promotes hyperactivation of receptor tyrosine kinase (RTK) signaling pathways in colorectal cancer (CRC) cells. Based on mass spectrometry-based interactomics, we identified key MACC1 interactors, including GRB2, SHP2, SHC1, and STAT5B, that preferentially associate with tyrosinephosphorylated residues Y365, Y379, and Y789. Site-directed mutagenesis of Y379 and Y789 reduced MACC1-induced migration, proliferation, and ERK phosphorylation. Using digital Western blotting (DigiWest), we observed a broad MACC1-dependent hyperactivation of downstream signaling effectors, including MEK, ERK, β-catenin, SRC, FAK, CREB, and VASP. Targeting MACC1-induced signaling with clinically relevant inhibitors effectively reversed MACC1-driven clonogenicity. Our findings support a role for MACC1 in promoting hyperactivation of RTK-associated signaling and reveal pharmacological vulnerabilities of potential relevance to metastasis-prone cancers characterized by elevated MACC1 expression. |
| Keywords: | MACC1, Colorectal Cancer, Metastasis, Receptor Tyrosine Kinase Signaling, Adaptor Protein, Tyrosine Phosphorylation, Protein–Protein Interaction, Signal Transduction |
| Source: | Biomolecules |
| ISSN: | 2218-273X |
| Publisher: | MDPI |
| Volume: | 16 |
| Number: | 9 |
| Page Range: | 1267 |
| Date: | September 2026 |
| Official Publication: | https://doi.org/10.3390/biom16091267 |
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