Chan Keefe T, Asokan Sreeja B, King Samantha J, Bo Tao, Dubose Evan S, Liu Wenjin, Berginski Matthew E, Simon Jeremy M, Davis Ian J, Gomez Shawn M, Sharpless Norman E, Bear James E
University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
J Cell Biol. 2014 Oct 27;207(2):299-315. doi: 10.1083/jcb.201404067.
Somatic inactivation of the serine/threonine kinase gene STK11/LKB1/PAR-4 occurs in a variety of cancers, including ∼10% of melanoma. However, how the loss of LKB1 activity facilitates melanoma invasion and metastasis remains poorly understood. In LKB1-null cells derived from an autochthonous murine model of melanoma with activated Kras and Lkb1 loss and matched reconstituted controls, we have investigated the mechanism by which LKB1 loss increases melanoma invasive motility. Using a microfluidic gradient chamber system and time-lapse microscopy, in this paper, we uncover a new function for LKB1 as a directional migration sensor of gradients of extracellular matrix (haptotaxis) but not soluble growth factor cues (chemotaxis). Systematic perturbation of known LKB1 effectors demonstrated that this response does not require canonical adenosine monophosphate-activated protein kinase (AMPK) activity but instead requires the activity of the AMPK-related microtubule affinity-regulating kinase (MARK)/PAR-1 family kinases. Inhibition of the LKB1-MARK pathway facilitated invasive motility, suggesting that loss of the ability to sense inhibitory matrix cues may promote melanoma invasion.
丝氨酸/苏氨酸激酶基因STK11/LKB1/PAR-4的体细胞失活存在于多种癌症中，包括约10%的黑色素瘤。然而，LKB1活性丧失如何促进黑色素瘤的侵袭和转移仍知之甚少。在源自具有激活的Kras和Lkb1缺失的黑色素瘤自体小鼠模型的LKB1缺失细胞以及匹配的重组对照中，我们研究了LKB1缺失增加黑色素瘤侵袭性运动的机制。本文使用微流控梯度室系统和延时显微镜，揭示了LKB1作为细胞外基质梯度（趋触性）而非可溶性生长因子信号（趋化性）的定向迁移传感器的新功能。对已知LKB1效应器的系统性扰动表明，这种反应不需要典型的腺苷单磷酸激活蛋白激酶（AMPK）活性，而是需要与AMPK相关的微管亲和力调节激酶（MARK）/PAR-1家族激酶的活性。抑制LKB1-MARK途径促进了侵袭性运动，这表明失去感知抑制性基质信号的能力可能促进黑色素瘤的侵袭。
