In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15

Abstract

A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10. Cell-based overexpression experiments revealed that this binding affected the maturation process and surface expression of the protease. Our current study shows that Tspan15 is abundantly expressed in mouse brain, where it specifically interacts with endogenous ADAM10. Tspan15 knockout mice did not reveal an overt phenotype but showed a pronounced decrease of the active and mature form of ADAM10, an effect which augmented with aging. The decreased expression of active ADAM10 correlated with an age-dependent reduced shedding of neuronal (N)-cadherin and the cellular prion protein. APP α-secretase cleavage and the expression of Notch-dependent genes were not affected by the loss of Tspan15, which is consistent with the hypothesis that different TspanC8s cause ADAM10 to preferentially cleave particular substrates. Analyzing spine morphology revealed no obvious differences between Tspan15 knockout and wild-type mice. However, Tspan15 expression was elevated in brains of an Alzheimer's disease mouse model and of patients, suggesting that upregulation of Tspan15 expression reflects a cellular response in a disease state. In conclusion, our data show that Tspan15 and most likely also other members of the TspanC8 family are central modulators of ADAM10-mediated ectodomain shedding in vivo.

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

“…This assumption is consistent with our finding that TSPAN15 expression had opposite effects on the shedding of NrCAM and APP. Likewise, a recent study demonstrated that TSPAN15 deficiency in mice reduced ADAM10 maturation and selectively reduced ADAM10 cleavage of N-cadherin and the prion protein, whereas APP cleavage by ADAM10 was not affected (Seipold et al, 2018). Whether TSPAN15 shows an altered expression in the AD patients that were treated with acitretin is not known, as the brains of these individuals are not available.…”

Tspan15 Is a New Stemness‐Related Marker in Hepatocellular Carcinoma

“…The antagonistic effects between Tspan5 and Tspan15 have been also observed on cell proliferation since Tspan5 may inhibit the cell cycle whereas our study supports Tspan15 as activating the cell cycle. Recently, in vivo regulation of ADAM10 by Tspan15 has been shown . The impact of Tspan15 expression in tumors can be important since the metalloprotease ADAM10 has been involved in the regulation of a variety of bioactive molecules and signaling pathways (e.g., Notch receptors, amyloid precursor protein APP, chemokines CX3CL1 and CXCL16, TNFalpha, EGFR ligands, growth factor receptors EGFR and VEGFR2, and various adhesion proteins) …”

F‐actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

“…Plasticity and stability of synaptic contacts rely on several factors, including transport and delivery of proteins and mRNA from the soma, local dendritic protein synthesis, surface diffusion of membrane proteins, recycling of synaptic proteins via the dendritic secretory trafficking system, and controlled disposal of “aged” molecules mediated by lysosomes, autophagosomes, and the proteasomal system (Hanus & Schuman, ; Mikhaylova et al , ; Bowen et al , ; Goo et al , ; Nirschl et al , ; Penn et al , ; Seipold et al , ). Various secretory trafficking organelles are present along dendrites and help to regulate the protein pool required for potentiation and stabilization of specific synaptic contacts (van Bommel & Mikhaylova, ).…”