Protein Kinase C α and β compensate for each other to promote stem cell factor-mediated KIT phosphorylation, mast cell viability and proliferation.
Protein Kinase C α and β compensate for each other to promote stem cell factor-mediated KIT phosphorylation, mast cell viability and proliferation.
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DOI：
10.1096/fj.202101838rrr
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发表时间：
2022-05
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肥大细胞（MC）从造血祖细胞发育并分化成位于结缔组织或粘膜组织内的成熟MC。虽然组织中MC的数量通常保持恒定，但炎症和哮喘会破坏这种稳态，导致MC增殖。了解这种增殖反应背后的信号事件可能会导致开发新的策略，以更好地管理过敏性疾病。MC的存活、增殖、分化和迁移均由MC生长因子、干细胞因子（SCF）通过其受体KIT维持。在这里，我们探讨了蛋白激酶C（PKC）冗余如何影响骨髓源性MC（BMMC）中MC增殖。我们发现SCF激活PKCα和PKCβ亚型，进而调节KIT磷酸化和内化。此外，PKCα和PKCβ激活p38丝裂原活化蛋白激酶（MAPK），该轴随后调节SCF诱导的MC细胞增殖。为了确定PKCα和PKCβ各自的作用，我们通过短发夹RNA（shRNA）敲除PKCα或PKCβ或两者，并分析KIT磷酸化、p38 MAPK磷酸化以及MC活力和增殖。令人惊讶的是，PKCα和PKCβ的下调均不影响MC的活力和增殖。相反，阻断PKCα和PKCβ可显著减弱SCF诱导的细胞活力和增殖，表明PKCα和PKCβ在SCF信号下游相互补偿，以增强MC活力和增殖。我们的研究结果不仅表明PKC经典亚型是SCF/MC介导的炎症和过敏性疾病的新治疗靶点，而且还强调了同时抑制PKCα和β亚型以防止MC增殖的重要性。
Mast cells (MCs) develop from hematopoietic progenitors and differentiate into mature MCs that reside within connective or mucosal tissues. Though the number of MCs in tissues usually remains constant, inflammation and asthma disturb this homeostasis, leading to proliferation of MCs. Understanding the signaling events behind this proliferative response could lead to the development of novel strategies for better management of allergic diseases. MC survival, proliferation, differentiation, and migration are all maintained by a MC growth factor, stem cell factor (SCF) via its receptor, KIT. Here, we explored how protein kinase C (PKC) redundancy influences MC proliferation in bone marrow‐derived MC (BMMC). We found that SCF activates PKCα and PKCβ isoforms, which in turn modulates KIT phosphorylation and internalization. Further, PKCα and PKCβ activate p38 mitogen activated protein kinase (MAPK), and this axis subsequently regulates SCF‐induced MC cell proliferation. To ascertain the individual roles of PKCα and PKCβ, we knocked down either PKCα or PKCβ or both via short hairpin RNA (shRNA) and analyzed KIT phosphorylation, p38 MAPK phosphorylation, and MC viability and proliferation. To our surprise, downregulation of neither PKCα nor PKCβ affected MC viability and proliferation. In contrast, blocking both PKCα and PKCβ significantly attenuated SCF‐induced cell viability and proliferation, suggesting that PKCα and PKCβ compensate for each other downstream of SCF signaling to enhance MC viability and proliferation. Our results not only suggest that PKC classical isoforms are novel therapeutic targets for SCF/MC‐mediated inflammatory and allergic diseases, but they also emphasize the importance of inhibiting both PKCα and β isoforms simultaneously to prevent MC proliferation.