The Role of GAB1 in Cancer

Abstract

GRB2-associated binder 1 (GAB1) is the inaugural member of the GAB/DOS family of pleckstrin homology (PH) domain-containing proteins. Upon receiving various stimuli, GAB1 transitions from the cytoplasm to the membrane where it is phosphorylated by a range of kinases. This event recruits SH2 domain-containing proteins like SHP2, PI3K's p85 subunit, CRK, and others, thereby activating distinct signaling pathways, including MAPK, PI3K/AKT, and JNK. GAB1-deficient embryos succumb in utero, presenting with developmental abnormalities in the heart, placenta, liver, skin, limb, and diaphragm myocytes. Oncogenic mutations have been identified in the context of cancer. GAB1 expression levels are disrupted in various tumors, and elevated levels in patients often portend a worse prognosis in multiple cancer types. This review focuses on GAB1's influence on cellular transformation particularly in proliferation, evasion of apoptosis, metastasis, and angiogenesis-each of these processes being a cancer hallmark. GAB1 also modulates the resistance/sensitivity to antitumor therapies, making it a promising target for future anticancer strategies.

Keywords: GAB1; angiogenesis; metastasis; therapy resistance; tumorigenesis.

Figure 1

GAB1 structure and partner binding sites. Schematic representation of the GAB1 structure. GAB1 has a pleckstrin homology (PH) domain at its amino-terminal end involved in the interaction with phosphatidylinositol 3,4,5-triphosphate (PIP3), a nuclear localization signal (NLS), tyrosine phosphorylation residues involved in the interaction with different proteins such as CRK, PLCγ, p85, and SHP2, a proline-rich region involved in the canonical and atypical interaction with GRB2, and the MET-binding domain (MBD) involved in the interaction with MET receptor.

Figure 2

GAB1 recruitment modes to activated receptors and major GAB1 signaling pathways. The direct mode of recruitment appears to be exclusive to the c-MET receptor (A), although it can also recruit GAB1 indirectly, like the other tyrosine kinase receptors (B). Physical interaction between GAB1 and CRK, SHP2, and p85 has been described, triggering the activation of the JNK, Ras/MAPK, and PI3K/AKT cell signaling pathways, respectively. ERK positively or negatively regulates GAB1 phosphorylation in a context-dependent manner, while SHP2 negatively regulates it. In addition, in response to HGF, PKC-α and PKC-β1 regulate GAB1 activation in a negative way. Red arrows denote negative regulation.

Figure 3

GAB1 is involved in cancer development and evolution. The GAB1 signaling pathway plays an important role in cancer pathobiology, including tumor cell proliferation, cell cycle, apoptosis evasion, tumor cell invasion and migration, tumor angiogenesis, and therapy resistance. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ accessed on 14 July 2023).

Figure 4

Boxplot of GAB1 mRNA level in normal and tumor human tissues. Bulk tissue gene expression for GAB1 from TNMplot (https://tnmplot.com/analysis/ (accessed on 14 July 2023)). Significant differences by the Mann–Whitney U test are marked with * and red legend.