Phospho-TACSTD2/TROP2 (Ser322) (F5T7U) Rabbit mAb #79865

TROP2 is a transmembrane glycoprotein encoded by gene TACSTD2 (tumor-associated calcium signal transducer 2). TROP2 was first discovered as a biomarker of invasive trophoblast cells and later reported in many types of cancer cells, in various organs during development, and adult stem cells during homeostasis (1,2). TROP2 has an extracellular domain with EGF thyroglobulin type-1 repeats, a transmembrane domain, and a short cytoplasmic tail with a HIKE domain containing a PIP2 binding site and PKC phosphorylation site (Ser303) (1-4). TROP2 functions by regulating multiple signaling pathways, including the interaction of its extracellular domain with integrin beta1 to regulate FAK signaling, the association of its transmembrane domain with claudin-1 and claudin-7 for tight junction formation, and the regulation of intracellular calcium release by its PIP2 binding and activation of the ERK/MAPK pathway (1,2,5-8). All these functions are important for its role in tumor proliferation, metastasis, and invasion (1,2). PKC can phosphorylate TROP2 at Ser303; the phosphorylation changes the cytoplasmic tail conformation and further promotes its signaling (9). TROP2 can be activated through intramembrane proteolysis first by TACE, followed by further cleavage by Presenilin 1 and Presenilin 2. The proteolysis process is required for its role in tumor cell proliferation (10,11).

TROP2 phosphorylation at Ser322 by PKCα/δ drives metastasis by disrupting both tight and adherens junctions (12,13). A phospho-mimetic (Ser322Glu) weakened the binding of TROP2 to claudin-7 and disrupted claudin-7 membrane localization in tight junctions (12). TROP2 c-terminus proteolytic cleavage is enhanced by Ser322 phosphorylation (13). A 13 kDa c-terminal TROP2 fragment translocates to the nucleus, directly interacting with the β-catenin/TCF4 complex to promote ZEB1 expression and E-cadherin downregulation (10,13). TROP2 can also directly bind to and drive cleavage of E-cadherin via Ezrin and ADAM10, respectively, disrupting E-cadherin association with the actin cytoskeleton and further enhancing cancer cell migration (14).