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

Acral melanoma (AM) is the most common subtype of melanoma in non-Caucasian populations, typically arising in weight-bearing areas of the sole. Currently, the majority of patients lack effective targeted therapeutic drugs. V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL), an adaptor protein, plays a pivotal role in the tumorigenesis and progression of various cancers. However, its function in the development of plantar acral melanoma remains unclear. In this study, clinical data and bioinformatic analyses reveal that CRKL is highly expressed in acral melanoma and is closely associated with Yes-associated protein (YAP) activity. Mechanistic studies further demonstrate that CRKL directly interacts with YAP, suppressing its ubiquitination and thereby preventing its proteasomal degradation. In addition, CRKL inhibits autophagy, further reducing YAP protein degradation. Notably, mechanical loading from weight-bearing activity is found to activate the YAP signaling pathway. Therefore, CRKL and mechanical stress synergistically to enhance YAP pathway activation, ultimately driving the initiation and progression of plantar melanoma. In conclusion, this study identifies CRKL as an oncogenic factor in plantar melanoma, elucidates the molecular basis underlying the predilection of this melanoma subtype for weight-bearing sites, and highlights CRKL as a potential therapeutic target for the treatment of plantar melanoma.