CRKL amplification synergizes with mechanical stress to dually activate YAP pathways, driving plantar melanoma progression.

Acral melanoma (AM) is a particularly aggressive subtype of melanoma, predominantly affecting non-Caucasian populations and frequently arising in weight-bearing areas like the sole. A significant challenge in treating AM is the current lack of effective targeted therapeutic drugs, leading to poor patient outcomes. V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL), an adaptor protein, is known to contribute to various cancers, but its specific role in the unique development and progression of plantar AM has remained largely unexplored, representing a critical knowledge gap.

Researchers conducted comprehensive analyses combining clinical data and bioinformatic approaches to assess CRKL expression in acral melanoma. Subsequent mechanistic studies investigated the interaction between CRKL and Yes-associated protein (YAP), a key oncogenic transcription factor. The team used various in vitro assays to determine how CRKL influences YAP's ubiquitination and proteasomal degradation. Additionally, they examined CRKL's impact on autophagy, another pathway involved in protein degradation, and explored the effect of mechanical loading on YAP signaling.

Clinical data and bioinformatic analyses consistently revealed that CRKL is highly expressed in acral melanoma and is closely associated with elevated YAP activity. Mechanistic investigations further elucidated the molecular basis of this association. They found that CRKL directly interacts with YAP, leading to a significant suppression of YAP's ubiquitination. This suppression effectively prevents YAP from undergoing proteasomal degradation, thereby increasing its stability and activity within cells. Furthermore, the study demonstrated that CRKL actively inhibits autophagy, a cellular process that would otherwise contribute to YAP protein degradation, providing an additional mechanism for YAP stabilization. > Notably, mechanical loading, mimicking the weight-bearing activity characteristic of plantar sites, was found to independently activate the YAP signaling pathway. This indicates a powerful synergy where CRKL and mechanical stress combine to enhance YAP pathway activation, ultimately driving both the initiation and progression of plantar melanoma.