Protein Kinase C α and β compensate for each other to promote stem cell factor‐mediated KIT phosphorylation, mast cell viability and proliferation

Abstract

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.

Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase C isozymes are involved in mGlu5a receptor internalization

“…As such, mGlu5 internalization is another example of functional redundancy within the PKC family (Table S1) (43)(44)(45)(46)(47)(48).…”

“…However, receptor internalization was not impacted by the absence of cPKCs or nPKCs, indicating involvement of isozymes from both subclasses that can compensate for each other. As such, mGlu 5 internalization is another example of functional redundancy within the PKC family ( Table S1 ) ( 43 , 44 , 45 , 46 , 47 , 48 ).

Figure 7 Schematic overview of the characterization of mGlu 5a -mediated PKC activation and mGlu 5a internalization.

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Novel strategies for cancer immunotherapy: counter-immunoediting therapy

“…TKIs as the mainstay of mast cell function inhibition have demonstrated their advantages in the treatment of tumors. For example, the inhibition of tyrosine kinase receptor signaling by CD117 will effectively inhibit mast cell recruitment; the inhibition of breakpoint cluster region (BCR)/ABL and protein kinase C (PKC) signaling has also demonstrated the clearance of mast cells and tumor suppression [125][126][127]. Additionally, the application of H1 receptor antagonists effectively inhibits mast cell infiltration, HIF-1α expression, and tumor growth within melanoma [128].…”

Elevated G-CSF, IL8, and HGF in patients with definite Meniere’s disease may indicate the role of NET formation in triggering autoimmunity and autoinflammation

“…SCF is the principal growth factor of mast cells and is secreted by fibroblasts, stromal cells, and endothelial cells. Through binding to the c-Kit receptor, SCF-induced signaling mediates inflammatory and allergic diseases with the autoimmune mechanism 60,61 .…”