MACC1, a Novel Player in Solid Cancer Carcinogenesis

Mudduluru, Giridhar; Ilm, Katharina; Dahlmann, Mathias; Stein, Ulf

doi:10.1007/978-3-319-53659-0_2

Cited by 3 publications

(1 citation statement)

References 121 publications

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“…Sketch of the domain structure of endocytic adaptor proteins including putative endocytic binding motifs. Domain structures were based on the following references: AP-2 [8], Stonin1/2 [25], FCHO1/2 and SGIP1 [26], AP180 and CALM [27], HIP1 and HIP1R [28], Epsin1/2/3 [29], Eps15 and Eps15R [30], ARH [31], Dab2 [32], Numb and Numbl [33], β-Arrestin1/2 [34], Hrb [35], TTP [36], MACC1 [37].…”

Section: Endocytic Adaptorsmentioning

confidence: 99%

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Tehran

López-Hernández

Maritzen

2019

Cells

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Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate the surface proteome and to recycle vesicular transmembrane proteins that strand at the plasma membrane after exocytosis. For efficient internalization, the cargo proteins need to be linked to the endocytic machinery via adaptor proteins such as the heterotetrameric endocytic adaptor complex AP-2 and a variety of mostly monomeric endocytic adaptors. In line with the importance of endocytosis for nutrient uptake, cell signaling and neurotransmission, animal models and human mutations have revealed that defects in these adaptors are associated with several diseases ranging from metabolic disorders to encephalopathies. This review will discuss the physiological functions of the so far known adaptor proteins and will provide a comprehensive overview of their links to human diseases.

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Section: Endocytic Adaptorsmentioning

confidence: 99%

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Tehran

López-Hernández

Maritzen

2019

Cells

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MACC1—the first decade of a key metastasis molecule from gene discovery to clinical translation

Radhakrishnan

Walther

Zincke

et al. 2018

Cancer Metastasis Rev

100

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The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis

et al. 2021

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Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.

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MACC1, a Novel Player in Solid Cancer Carcinogenesis

Cited by 3 publications

References 121 publications

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

MACC1—the first decade of a key metastasis molecule from gene discovery to clinical translation

The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis

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