Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea.
Cells. 2021 Dec 28;11(1):78. doi: 10.3390/cells11010078.
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.
LIM 激酶（LIMK1 和 LIMK2）作为下游效应物，以及 Rho 相关蛋白激酶（ROCK），是肌动蛋白动态的调节剂，对多种细胞功能都有影响。LIM 激酶通过磷酸化丝切蛋白和随后的肌动蛋白细胞骨架重排参与平滑肌收缩，从而影响男性泌尿生殖系统的功能。尽管 LIMK1 和 LIMK2 作为丝氨酸蛋白激酶具有序列相似性，但不同的组织分布模式和细胞周期进程中的不同定位表明每种激酶具有其他生物学功能。在减数分裂和有丝分裂过程中，LIMK1/2-丝切蛋白信号促进了配子发生和肌动蛋白细胞骨架之间的协调染色质重塑。LIMK2 转录本的剪接变体仅在睾丸中表达。此外，用 LIMK2 特异性抗体检测到的阳性信号主要存在于精母细胞和早期圆形精子细胞等生殖细胞的分化阶段的细胞核中。LIMK2 在正常精子发生中起着至关重要的作用，例如青春期后精子发生的减数分裂过程。另一方面，文献证据表明 LIMK1 表达的减少增强了 ROCK 抑制剂对人前列腺平滑肌收缩的抑制作用。LIMK1 可能在良性前列腺增生症男性的尿道梗阻和膀胱出口梗阻中发挥作用。此外，尿道狭窄时 LIMK1 表达减少。LIMK1 表达减少导致尿道成纤维细胞增殖和迁移受损。此外，激活的 LIMK2-丝切蛋白通路有助于海绵体神经损伤后的海绵体纤维化。最近的证据表明，在海绵体神经损伤后的即刻损伤期短期抑制 LIMK2 可防止海绵体纤维化并改善大鼠模型的勃起功能。此外，慢性抑制 LIMK2-丝切蛋白通路可通过抑制海绵体中的纤维化显著抑制海绵体静脉闭塞性功能障碍，这是前列腺切除术后勃起功能障碍的主要病理生理机制。总之，LIM 激酶-丝切蛋白通路似乎通过肌动蛋白细胞骨架重排在男性泌尿生殖系统功能中发挥作用，并有助于几种泌尿生殖系统疾病的发病机制。因此，LIM 激酶可能是泌尿生殖系统疾病的潜在治疗靶点。
