The Role of LIM Kinase in the Male Urogenital System

Abstract

The LIM kinases (LIMK1 and LIMK2), known as downstream effectors, and the Rho-associated protein kinase (ROCK), a regulator of actin dynamics, have effects on a diverse set of cellular functions. The LIM kinases are involved in the function of the male urogenital system by smooth muscle contraction via phosphorylation of cofilin and subsequent actin cytoskeleton reorganization. Although LIMK1 and LIMK2 share sequence similarities as serine protein kinases, different tissue distribution patterns and distinct localization during cell cycle progression suggest other biological functions for each kinase. During meiosis and mitosis, the LIMK1/2–cofilin signaling facilitates the orchestrated chromatin remodeling between gametogenesis and the actin cytoskeleton. A splicing variant of the LIMK2 transcript was expressed only in the testis. Moreover, positive signals with LIMK2-specific antibodies were detected mainly in the nucleus of the differentiated stages of germ cells, such as spermatocytes and early round spermatids. LIMK2 plays a vital role in proper spermatogenesis, such as meiotic processes of spermatogenesis after puberty. On the other hand, the literature evidence revealed that a reduction in LIMK1 expression enhanced the inhibitory effects of a ROCK inhibitor on the smooth muscle contraction of the human prostate. LIMK1 may have a role in urethral obstruction and bladder outlet obstruction in men with benign prostatic hyperplasia. Moreover, LIMK1 expression was reduced in urethral stricture. The reduced LIMK1 expression caused the impaired proliferation and migration of urethral fibroblasts. In addition, the activated LIMK2–cofilin pathway contributes to cavernosal fibrosis after cavernosal nerve injury. Recent evidence demonstrated that short-term inhibition of LIMK2 from the immediate post-injury period prevented cavernosal fibrosis and improved erectile function in a rat model of cavernosal nerve injury. Furthermore, chronic inhibition of the LIMK2–cofilin pathway significantly restrained the cavernosal veno-occlusive dysfunction, the primary pathophysiologic mechanism of post-prostatectomy erectile dysfunction through suppressing fibrosis in the corpus cavernosum. In conclusion, the LIM kinases–cofilin pathway appears to play a role in the function of the male urogenital system through actin cytoskeleton reorganization and contributes to the pathogenesis of several urogenital diseases. Therefore, LIM kinases may be a potential treatment target in urogenital disorder.

Comparative Proteome Analysis of Four Stages of Spermatogenesis in the Small-Spotted Catshark (Scyliorhinus canicula), Using High-Resolution NanoLC-ESI-MS/MS

“…Roles of other proteins such as “optineurin”, a ubiquitin-binding adaptor protein; the “pregnancy zone protein”, a chaperone protein maintaining protein homeostasis during pregnancy, the “Programmed cell death 6-interacting protein” or “Testis, prostate and placenta-expressed protein” or “Maestro heat-like repeat family member 1” during spermatogenesis remain to be clarified. While for others, a role during spermatogenesis has been explored such as for prosaposin (PSAP) involved in the development of the reproductive system, cofilin as an actin depolymerizing factor, progranulin (PGRN) an acrosomal glycoprotein synthesized during spermatogenesis, centrin 3 a member of the centrosome protein family, or “Spermatogenesis-associated protein 6” (SPATA6) …”

Diallyl disulfide downregulating RhoGDI2 induces differentiation and inhibit invasion via the Rac1/Pak1/LIMK1 pathway in human leukemia HL‐60 cells

“…The primary features are promoting cell viability and suppressing cell adhesion 36 . LIMK1 which is one of the downstream molecules of the Rho family of small GTPases with their effector PAK1, is relevant in the migration invasion of prostate and breast cancers, osteosarcoma and other cancers 37–40 . A variety of recent researchers have found that a couple of various medicines, such as sea cucumber Cucumaria frondosa, could modulate cytoskeletal reconstruction through Rac1/PAK1/LIMK1 signaling axis, thereby suppressing the adhesion and migration of neoplastic cells 41 .…”

Pharmacotherapy of urethral stricture

“…Urethral stricture is characterized by fibrotic changes ( Figure 1a ), and common pathological features of urethral stricture include excessive fibroblast proliferation, extracellular matrix (ECM) abnormalities, and collagen synthesis within the urethral spongiosa. 18 Among these, ECM abnormalities feature changes in the composition of glycosaminoglycans, 19 accumulation of transforming growth factor-β (TGF-β), and dysregulation of collagen deposition and collagen maturation. 20 It is now understood that collagen I and III are the main components of the ECM, and the higher percentage of type I/III in the lumen of urethral stricture than that in the normal urethral lumen account for the poor compliance of urethral stricture scar tissue fibrosis.…”