Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface

Abstract

ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, ADAM9 can cleave several transmembrane proteins, thereby shedding their ectodomains from the cell surface. Moreover, ADAM9 regulates cell behavior by binding cell-surface receptors such as integrin and membrane-type matrix metalloproteases. Because these functions are mainly restricted to the cell surface, understanding the mechanisms regulating ADAM9 localization and activity at this site is highly important. To this end, we here investigated how intracellular trafficking regulates ADAM9 availability at the cell surface. We found that ADAM9 undergoes constitutive clathrin-dependent internalization and subsequent degradation or recycling to the plasma membrane. We confirmed previous findings of an interaction between ADAM9 and the intracellular sorting protein, sorting nexin 9 (SNX9), as well as its close homolog SNX18. Knockdown of either SNX9 or SNX18 had no apparent effects on ADAM9 internalization or recycling. However, double knockdown of SNX9 and SNX18 decreased ADAM9 internalization significantly, demonstrating a redundant role in this process. Moreover, SNX9 knockdown revealed a nonredundant effect on overall ADAM9 protein levels, resulting in increased ADAM9 levels at the cell surface, and a corresponding increase in the shedding of Ephrin receptor B4, a well-known ADAM9 substrate. Together, our findings demonstrate that intracellular SNX9-mediated trafficking constitutes an important ADAM9 regulatory pathway.

Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects

“…As a membrane-anchored protein of the A-Disintegrin and Metalloproteinase (ADAM) protein family, the overexpression of ADAM9 in solid tumors has been correlated with aggressive tumor phenotypes and unfavorable clinical prognosis ( 149 ). ADAM9 may implicated in tumor progression and invasion either via non-proteolytic mechanisms that include interactions between tumor cells and endothelial or peritumoral stromal cells ( 150 ), or proteolytic mechanisms that involve an enzymatic modification called “shedding” or processing of cell-surface proteins ( 151 ). The value of ADAM9 inhibition in reducing migration and invasion of different solid tumors has been established ( 152 , 153 ).…”

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

“…Cell surface levels of ADAM9 are regulated via cytosolic interaction with sorting nexins, which in turn has an effect on ADAM9 activity (Mygind et al ., ). ADAM9 has been found to shed various cell surface proteins.…”

A robust gene expression signature to predict proteasome inhibitor benefit in Multiple Myeloma

“…CLIP1 is involved in microtubule-kinetochore attachment and plays a role in proper chromosome alignment during mitosis 19,20 and has been associated with cancer progression and chemotherapy resistance 21 , though not in relation to MM. SNX9 is described to play an important role in trafficking ADAM9 to the cell surface 22 . ADAM9 is expressed in MM cells and induces IL6 production by osteoblasts, potentially creating a more permissive bone marrow environment for MM cell proliferation 23 .…”