Stalling PTKs in their tracks

A key enzyme found in all mammalian tissues plays an important role in reining in the activity of certain protein tyrosine kinases (PTKs) just before cell division, Monash University researchers have found.

The enzyme, T cell protein tyrosine phosphatase (TCPTP), regulates signalling in the PTK pathways, turning them off in response to damaged DNA, thus preventing the cell from moving into the DNA replication phase.

Overactive PTK pathways have been linked with several aggressive cancers, including colon, breast and lung cancers.

In cells lacking TCPTP, the PTK pathways remain activated, and may allow cancer cells to bypass the molecular checkpoints that ensure proper cell-cycle progression, the researchers, led by Monash’s Associate Professor Tony Tiganis, report in yesterday’s edition of Cancer Cell .

“[Checkpoints] facilitate orderly cell-cycle progression and ensure the faithful transmission of replicated DNA to daughter cells,” the researchers write. “Failure of such checkpoints can lead to genomic instability that is associated with many human cancers.”

In the face of damaged DNA, the checkpoints suppress progression into the replication phase, known as the synthesis or S phase, and also co-ordinate DNA repair.

However, several PTKs, including JAKs 1 and 3 and Src-family PTKs (SFKs), and their substrates STAT3 and cyclin D1, are frequently hyperactivated in a wide variety of cancers, promoting cell-cycle progression and proliferation.

The Monash team found that inactivation of these PTKs by TCPTP inhibits the expression of cyclin 1, the oncogene that regulates the transition into the S phase, thus stalling progression.

Cells lacking TCPTP showed continued PTK signalling and elevated levels of cyclin D1, which may lead to unscheduled cell division, with DNA distributed unevenly in the daughter cells.

The team will now look at human cancer cells to see if they contain low levels of TCPTP.

Tiganis said that with drugs already available to inhibit particular PTKs, this research could help in fine-tuning the timing of when and how those drugs are administered.

DNA Replication Stalling Attenuates Tyrosine Kinase Signaling to Suppress S Phase Progression is published in Cancer Cell.