Metabolic Activation-related CD147-CD98 Complex

Abstract

Cell surface CD147 protein promotes production of matrix metalloproteinases and hyaluronan, associates with monocarboxylate transporters and integrins, and is involved in reproductive, neural, inflammatory, and tumor functions. Here we combined covalent cross-linking, mass spectrometric protein identification, and co-immunoprecipitation to show selective CD147 association with three major types of transporters (CD98 heavy chain (CD98hc)-L-type amino acid transporter, ASCT2, and monocarboxylate transporters) as well as a regulator of cell proliferation (epithelial cell adhesion molecule). In the assembly of these multicomponent complexes, CD147 and CD98hc play a central organizing role. RNA interference knock-down experiments established a strong connection between CD147 and CD98hc expression and a strong positive association of CD147 (and CD98hc) with cell proliferation. As the CD147-CD98hc complex and proliferation diminished, AMP-activated protein kinase (a cellular "fuel gauge") became activated, indicating a disturbance of cellular energy metabolism. Our data point to a CD147-CD98 cell surface supercomplex that plays a critical role in energy metabolism, likely by coordinating transport of lactate and amino acids. Furthermore we showed how covalent cross-linking, together with mass spectrometry, can be used to identify closely associated transmembrane proteins. This approach should also be applicable to many other types of transmembrane proteins besides those associated with CD98hc and CD147.

Relationship between [ 14 C]MeAIB uptake and amino acid transporter family gene expression levels or proliferative activity in a pilot study in human carcinoma cells: Comparison with [ 3 H]methionine uptake

“…The intracellular glutamine supply is maintained via the intracellular Na + -dependent amino acid transporter ASCT2 that helps facilitate LAT1 function. The interplay between LAT1, ASCT2, and 4F2hc is thought to be important in controlling cancer cell metabolism [40]. For example, co-expression of LAT1 with ASCT2 has been shown in lung cancer, and this co-expression, but not the sole expression of LAT1 or ASCT2, is strongly related to prognosis [41].…”

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…46,47 On the other hand, the MCT1-CD147 complex is known to behave as a scaffold for other proteins involved in cell migration and invasion. 48 The composition of these supercomplexes is cell type-dependent and could logically be influenced by the cell environment and MCT1 expression and activity (conformation change).…”

Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

“…MCT activity is also fundamental to the "Warburg effect" (Warburg, 1956), a glycolytic phenotype that is common to most malignant cancers and associated with resistance to therapies (Gatenby and Gillies, 2004;Koukourakis et al, 2006;Tredan et al, 2007). MCT-emmprin interactions have been demonstrated in human breast carcinoma cells (Gallagher et al, 2007;Xu and Hemler, 2005).…”

“…Interestingly, another common marker for cancer stem-like cells is EpCAM, also known as ESA (Al-Hajj et al, 2003;Dalerba et al, 2007b;Li et al, 2007a). EpCAM is a binding partner of emmprin (Xu and Hemler, 2005), implying that emmprin may also be associated with cancer stem-like cells. Moreover, it has been observed that breast carcinoma cells that express both CD44 and EpCAM are more malignant than cells expressing CD44 but not EpCAM (Al-Hajj et al, 2003).…”