The tumor-suppressor genes LKB1, PTEN, PRKAR1A exert inhibitory effects on signaling through the TSC complex that inactivates mTOR, while SHP2 gain-of-function mutations also lead to downstream mTOR activation. Each of genes is mutated in distinct syndromes that are characterized by the development of lentigines and other skin lesions. Abbreviations: LKB1, serine/threonine kinase 11; AMPK, AMP-activated protein kinase; PTEN, phosphatase and tensin homolog; P13K, 1-phosphatidylinositol 3-kinase; AKT, protein kinase B; NF1; neurofibromatosis type 1MEK, mitogen activated protein kinase kinase; ERK, extracellular signal-regulated kinase; TSC1; tuberous sclerosis 1; TSC2; tuberous sclerosis 2; mTOR, mammalian target of rapamycin.