Fer and FerT: A New Regulatory Link between Sperm and Cancer Cells.

Fer and its sperm and cancer specific variant, FerT, are non-receptor tyrosine kinases which play roles in cancer progression and metastasis. Recent studies have shed light on the regulatory role of these kinases in ensuring proper sperm function. Comparison of the regulatory cascades in which Fer and FerT are engaged in sperm and cancer cells presents an interesting picture, in which similar regulatory interactions of these enzymes are integrated in a similar or different regulatory context in the two cell types. These diverse compositions extend from the involvement of Fer in modulation of actin cytoskeleton integrity and function, to the unique regulatory interactions of Fer with PARP-1 and the PP1 phosphatase. Furthermore, recent findings link the metabolic regulatory roles of Fer and FerT in sperm and cancer cells. In the current review, we discuss the above detailed aspects, which portray Fer and FerT as new regulatory links between sperm and malignant cells. This perspective view can endow us with new analytical and research tools that will deepen our understanding of the regulatory trajectories and networks that govern these two multi-layered systems.

The Fer tyrosine kinase protects sperm from spontaneous acrosome reaction.

The physiological acrosome reaction occurs after mammalian spermatozoa undergo a process called capacitation in the female reproductive tract. Only acrosome reacted spermatozoon can penetrate the egg zona-pellucida and fertilize the egg. Sperm also contain several mechanisms that protect it from undergoing spontaneous acrosome reaction (sAR), a process that can occur in sperm before reaching proximity to the egg and that abrogates fertilization. We previously showed that calmodulin-kinase II (CaMKII) and phospholipase D (PLD) are involved in preventing sAR through two distinct pathways that enhance F-actin formation during capacitation. Here, we describe a novel additional pathway involving the tyrosine kinase Fer in a mechanism that also prevents sAR by enhancing actin polymerization during sperm capacitation. We further show that protein-kinase A (PKA) and the tyrosine-kinase Src, as well as PLD, direct Fer phosphorylation/activation. Activated Fer inhibits the Ser/Thr phosphatase PP1, thereby leading to CaMKII activation, actin polymerization, and sAR inhibition.