SRC fine‐tunes ADAM10 shedding activity to promote pituitary adenoma cell progression

Abstract

A disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) is a metalloproteinase known to modulate the progression of several types of tumor. However, the role played by ADAM10 in pituitary adenomas is currently unknown, and what factors orchestrate the activation of ADAM10 in this kind of tumor is also unclear. Here, we found that SRC kinase is an ADAM10‐interacting partner and that SRC kinase activity is required for this interaction. As a new positive regulator promoting the shedding activity of ADAM10, SRC could compete with calmodulin 1 (CALM1) for ADAM10 binding in a mutually exclusive manner. Strikingly, the interaction between ADAM10 and CALM1 is regulated by SRC activity. Furthermore, we proved that the cytoplasmic region of ADAM10 is required for the shedding activity of ADAM10 upon SRC activation. As a proof‐of‐concept, we discovered that the combination of ADAM10 and SRC inhibitors can inhibit cell proliferation and migration to a great extent. Thus, our findings shed light on a novel therapeutic strategy to block the tumorigenesis and migration of pituitary adenoma.

Pituitary Adenomas and Invasiveness from Anatomo-Surgical, Radiological, and Histological Perspectives: A Systematic Literature Review

“…The expression levels of other matrix metalloproteinases has been widely investigated. Upregulation of MMP-2, MMP-9, and ADAM-10 have been more frequently associated with tumor invasion [55,57,[151][152][153]. Accordingly, metalloproteinase inhibitors (e.g., TIMP-3) are down-regulated in invasive PitNETs [154].…”

Ca2+ Signaling and Src Functions in Tumor Cells

“…The metalloprotease ADAM10 (disintegrin and metalloproteinase domain-containing protein 10) is regulated by c-Src and CaM [121][122][123]. ADAM10 was overexpressed in high-grade pituitary adenoma cells, and the invasiveness of these tumors was explained, at least in part, by the c-Src/CaM-mediated mechanisms [121,122].…”

“…The metalloprotease ADAM10 (disintegrin and metalloproteinase domain-containing protein 10) is regulated by c-Src and CaM [121][122][123]. ADAM10 was overexpressed in high-grade pituitary adenoma cells, and the invasiveness of these tumors was explained, at least in part, by the c-Src/CaM-mediated mechanisms [121,122]. The inactive form of this proteinase, denoted pro-ADAM10, was activated upon Ca 2+ influx by reducing the Ca 2+ /CaM-pro-ADAM10 interaction, and the activated proteinase subsequently induced the cleavage of the adhesion molecules CD44 and L1CAM (cell adhesion molecule L1) [123], disrupting the cell-cell interaction, detaching cells from the extracellular matrix, and thus enhancing the invasiveness of the tumor cells.…”

ADAM10-a “multitasker” in sepsis: focus on its posttranslational target

“…In CLP-induced polymicrobial sepsis, treatment with the c-Src-SH3 peptide in a complex with β-glucans (SPG) dramatically reduces the mortality involved in controlling the excessive production of ROS and inflammation [ 121 ]. SRC has been shown to bind directly to the cytoplasmic domain of ADMA10, limiting cell proliferation and migration to a great extent in pituitary adenoma [ 122 ]. As a putative ADAM10-interacting SH3 domain interactor, Lck can bind with both phosphorylated and unphosphorylated forms of ADAM10 [ 117 , 123 ].…”