Research ArticleCancer

Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells

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Science Signaling  20 Aug 2019:
Vol. 12, Issue 595, eaav2041
DOI: 10.1126/scisignal.aav2041

Semaphorins in reverse

Members of the large family of semaphorins guide cell migration. As ligands, some semaphorins are implicated in promoting cancer progression and angiogenesis. Gurrapu et al. found an alternative mechanism in which semaphorin 4C (Sema4C) acts as a receptor to promote metastasis. In response to interaction with the extracellular domain of PlexinB2 (which is a receptor when Sema4C acts as a ligand), transmembrane-resident Sema4C intracellularly interacted with and activated TGF-β receptors in invasive breast cancer cell lines. Subsequent changes in gene expression suppressed mesenchymal features and promoted metastasis in a mouse model of disseminated-cell seeding and growth. These findings reveal one way in which Sema4C promotes the cellular plasticity necessary for metastatic disease.


Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands (“forward” mode) and signaling receptors (“reverse” mode); however, reverse semaphorin signaling in cancer is relatively less understood. Here, we identified a previously unknown function of transmembrane semaphorin 4C (Sema4C), acting in reverse mode, to elicit nonconventional TGF-β/BMP receptor activation and selective SMAD1/5 phosphorylation. Sema4C coimmunoprecipitated with TGFBRII and BMPR1, supporting its role as modifier of this pathway. Sema4C reverse signaling led to the increased abundance of ID1/3 transcriptional factors and to extensive reprogramming of gene expression, which suppressed the typical features of the epithelial-mesenchymal transition in invasive carcinoma cells. This phenotype was nevertheless coupled with burgeoning metastatic behavior in vivo, consistent with evidence that Sema4C expression correlates with metastatic progression in human breast cancers. Thus, Sema4C reverse signaling promoted SMAD1/5- and ID1/3-dependent gene expression reprogramming and phenotypic plasticity in invasive cancer cells.

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