Table 3.

Studies reporting TMEFF2 function.

Function	Oncogenic vs. Onco-Suppressive	Disease or Process	Reference
TMEFF2 binds and inhibits PDGF-AA through its follistatin-like domains.	Onco-suppressive	Several cancers	[8]
TMEFF2 promotes survival of hippocampal and mesencephalic neurons in primary culture.	Neither but pro-growth	Neuronal development	[4]
Tomoregulin mildly activates erbB-4 receptors in MKN28 gastric cancer cells.	Oncogenic	Gastric cancer	[11]
TMEFF2 inhibits Akt phosphorylation and production of ACTH in response to CRH stimulation in AtT20 glioma cells. TMEFF2 decreases the proliferation of AtT20 cells.	Onco-suppressive	Glioma	[6]
(i) TMEFF2 is specifically upregulated in OPCs at onset of cell differentiation, but it is dispensable in the process. (ii) TMEFF2 weakly interacts with PDGFA but does not prevent the action of PDGFA on its receptor in HEK293T cells. (iii) TMEFF2 overexpression increases ERK1/2 phosphorylation in HEK293T cells.	Neither but pro-growth	Development	[54]
Tomoregulin mRNA is expressed in mouse embryo at E-11, increases gradually till E-15 and stabilizes through to E-17.	Neither	Development	[11]
TMEFF2 is regulated by androgens in prostate cancer and inhibits the proliferation of DU145 and PC3 prostate cancer cells.	Onco-suppressive	Prostate cancer	[46]
TMEFF2mAb conjugated cytotoxic drug Pr1-vcMMAE effectively reduced the tumour size in LNCap and CWR22 xenograft with minimal toxicity.	Potentially oncogenic	Prostate cancer	[47]
β-emitting isotope 90Y-labelled TMEFF2 mAB 2H8 effectively reduces LNCaP xenograft size and is well tolerated.	Potentially oncogenic	Prostate cancer	[15]
TMEFF2 is expressed on the cell surface, and it is internalized and recycled in lysosomes. TMEFF2 mAB is complexed with cytotoxin saporin, and it causes death of TMEFF2-Stable PC3 cells.	Potentially oncogenic	Prostate cancer	[52]
TMEFF2 binds amyloid-β protein, its precursor AβPP and the neurotoxic oligomeric forms of amyloid-β protein AβPOs in vitro and in vivo. TMEFF2 protects N2a cells from neurotoxicity induced by AβPO.	None	Alzheimer’s disease	[7]
TMEFF2 ectodomain shedding is triggered by TNFα, is brought about by ADAM10 and ADAM17, and increases proliferation of HEK293T cells. TMEFF2 causes phosphorylation of ERK1/2.	Neither but pro-growth	Prostate cancer	[5]
TMEFF2 is a substrate for membrane anchored serine proteases (TTSPs) matriptase-1 and hepsin.	Depends on proteolytic processing of TMEFF2	Prostate cancer	[17]
Full-length TMEFF2 reduces cell proliferation and sensitises HEK293T cells to apoptosis, binds and augments sarcosine dehydrogenase (SRDH) activity and reduces sarcosine levels, leading to inhibition of cell migration. The TMEFF2 ectodomain does the opposite.	Ectodomain: oncogenic Full-length: onco-suppressive	Prostate cancer	[53]
Full-length TMEFF2 (i) reduces the expression of integrins αv, β1 and β3; (ii) inhibits RHOA activation; (iii) inhibits phosphorylation of the focal adhesion kinase (FAK); and (iv) reduces cell migration. Deletion of putative G-protein domain prevents all of the above.	Onco-suppressive	Prostate cancer	[22]
TMEFF2 reduces invasiveness of 22Rv1 prostate cancer cells through modulation of one-carbon metabolism. TMEFF2 interacts with the cytoskeleton.	Onco-suppressive	Prostate cancer	[20]
HPP1 induces apoptosis and causes changes in morphology and reduction in cell proliferation in HCT-116 colorectal cells through activation of the STAT1 pathway.	Onco-suppressive	Colorectal cancer	[55]
HPP1 activates JAK-STAT interferon pathways to induce apoptosis and to reduce proliferation of HCT-116 cells. TMEFF2 overexpression marginally sensitized HCT-116 cells to INF-α-induced cell death.	Onco-suppressive	Colorectal cancer	[56]
TMFF2 decreases STAT3 phosphorylation through its interaction with SHP1 in gastric cancer. STAT3 directly binds to the TMEFF2 promoter and represses its transcription.	Onco-suppressive	Gastric cancer	[42]
TMEF2 binds SHP-1 in gastric cancer, induces cell cycle arrest and apoptosis and prevents DNA damage.	Onco-suppressive	Gastric cancer	[41]