FHIT

The protein encoded by this gene is a P1-P3-bis(5'-adenosyl) triphosphate hydrolase involved in purine metabolism. This gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas. The encoded protein is also a tumor suppressor, as loss of its activity results in replication stress and DNA damage. [provided by RefSeq, Aug 2017]

Fragile Histidine Triad

Possesses dinucleoside triphosphate hydrolase activity (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908, PubMed:9543008).

Cleaves P1-P3-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908, PubMed:9543008).

Can also hydrolyze P1-P4-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP (PubMed:8794732).

Exhibits adenylylsulfatase activity, hydrolyzing adenosine 5'-phosphosulfate to yield AMP and sulfate (PubMed:18694747).

Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2 (PubMed:18694747).

Exhibits adenylylsulfate-ammonia adenylyltransferase, catalyzing the ammonolysis of adenosine 5'-phosphosulfate resulting in the formation of adenosine 5'-phosphoramidate (PubMed:26181368).

Also catalyzes the ammonolysis of adenosine 5-phosphorofluoridate and diadenosine triphosphate (PubMed:26181368).

Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5 (PubMed:18077326).

Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways (PubMed:16407838).

Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis (PubMed:15313915).

Induction of apoptosis depends on the ability of FHIT to bind P1-P3-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca2+ transporters, enhancing mitochondrial calcium uptake (PubMed:12574506, PubMed:19622739).

Functions as tumor suppressor (By similarity).

Diadenosine triphosphate catabolic process Source: UniProtKB
Intrinsic apoptotic signaling pathway by p53 class mediator Source: UniProtKB
Negative regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
Purine nucleotide metabolic process Source: UniProtKB

Mitochondrion; Cytoplasm; Nucleus

A chromosomal aberration involving FHIT has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT in its 5-prime non-coding region, it is unlikely that FHIT is causally related to renal or other malignancies.
Associated with digestive tract cancers. Numerous tumor types are found to have aberrant forms of FHIT protein due to deletions in a coding region of chromosome 3p14.2 including the fragile site locus FRA3B.

Phosphorylation at Tyr-114 by SRC is required for induction of apoptosis.