The growth factor progranulin plays a critical role in bladder cancer by modulating tumor cell motility and invasion. Progranulin regulates remodeling of the actin cytoskeleton by interacting with drebrin, an actin binding protein that regulates tumor growth. We previously discovered that progranulin depletion inhibits epithelial-to-mesenchymal transition and markedly reduces in vivo tumor growth. Moreover, progranulin depletion sensitizes urothelial cancer cells to cisplatin treatment, further substantiating a pro-survival function of progranulin. Until recently, the progranulin signaling receptor remained unidentified, precluding a full understanding of progranulin action in tumor cell biology. We recently identified EphA2, a member of a large family of receptor tyrosine-kinases, as the functional receptor for progranulin. However, it is not established whether EphA2 plays an oncogenic role in bladder cancer. Here we demonstrate that progranulin, and not ephrin-A1, the canonical ligand for EphA2, is the predominant EphA2 ligand in bladder cancer. Progranulin evoked Akt- and Erk1/2-mediated EphA2 phosphorylation at Ser897, which could drive bladder tumorigenesis. We discovered that EphA2 depletion severely blunted progranulin-dependent motility and anchorage-independent growth, and sensitized bladder cancer cells to cisplatin treatment. We further defined the mechanisms of progranulin/EphA2-dependent motility by identifying liprin-α1 as a novel progranulin-dependent EphA2 interacting protein and establishing its critical role in cell motility. The discovery of EphA2 as the functional signaling receptor for progranulin and the identification of novel downstream effectors offer a new avenue for understanding the underlying mechanism of progranulin action and may constitute novel clinical and therapeutic targets in bladder cancer.

生长因子颗粒蛋白前体通过调节肿瘤细胞运动和侵袭在膀胱癌中发挥关键作用。颗粒蛋白前体通过与 drebrin（一种调节肿瘤生长的肌动蛋白结合蛋白）相互作用来调节肌动蛋白细胞骨架的重塑。我们以前发现颗粒蛋白前体耗竭抑制上皮间质转化并显着减少体内肿瘤生长。此外，颗粒蛋白前体耗竭使尿路上皮癌细胞对顺铂治疗敏感，进一步证实了颗粒蛋白前体的促存活功能。直到最近，颗粒蛋白前体信号受体仍未确定，无法完全了解颗粒蛋白前体在肿瘤细胞生物学中的作用。我们最近确定了 EphA2，它是受体酪氨酸激酶大家族的成员，是颗粒蛋白原的功能受体。然而，尚未确定 EphA2 是否在膀胱癌中起致癌作用。在这里，我们证明颗粒蛋白原，而不是 ephrin-A1（EphA2 的典型配体）是膀胱癌中的主要 EphA2 配体。颗粒蛋白前体在 Ser897 处诱发 Akt 和 Erk1/2 介导的 EphA2 磷酸化，这可能会驱动膀胱肿瘤发生。我们发现 EphA2 耗竭严重削弱了颗粒蛋白前体依赖性运动和锚定非依赖性生长，并使膀胱癌细胞对顺铂治疗敏感。我们通过将 liprin-α1 鉴定为一种新型的颗粒蛋白前体依赖性 EphA2 相互作用蛋白并确定其在细胞运动中的关键作用，进一步定义了颗粒蛋白前体/EphA2 依赖性运动的机制。EphA2 作为颗粒蛋白前体的功能性信号受体的发现和新型下游效应器的发现为理解颗粒蛋白前体作用的潜在机制提供了新途径，并可能构成膀胱癌的新临床和治疗靶点。