Cells, the fundamental building blocks of all living organisms, constantly communicate with each other and their environment. This communication occurs through intricate molecular pathways known as cell signaling. Proteins are the primary players in these pathways, acting as messengers and responders to ensure cells grow, divide, specialize, and even undergo programmed death in a coordinated manner.
The ERK5 Protein
Extracellular signal-regulated kinase 5 (ERK5) is a protein within the Mitogen-Activated Protein Kinase (MAPK) family. MAPKs are enzymes that relay signals from the cell surface to the cell’s internal machinery, including the nucleus. ERK5, also known as BMK1 or MAPK7, is notably larger, approximately double the size of other ERK proteins.
This larger size is due to an extended C-terminal end. This C-terminal tail contains a nuclear localization signal (NLS), two proline-rich regions, and a transcriptional activation domain (TAD). While the N-terminal part of ERK5, which contains its kinase domain, shares similarity with other MAPKs like ERK1/2, its distinct C-terminal tail provides unique functional capabilities.
How ERK5 Functions
ERK5 activation begins with the upstream kinase MEK5 (MAPK/ERK kinase 5), in response to various extracellular signals. These stimuli include growth factors, hormones, cytokines, and cellular stressors such as oxidative stress, high osmolarity, and fluid shear stress. MEK5 phosphorylates ERK5 at a threonine-glutamic acid-tyrosine (TEY) motif within its kinase domain, activating it.
Upon activation, ERK5 undergoes a conformational change, separating its N-terminal kinase domain from its C-terminal region. This allows ERK5 to translocate from the cytoplasm into the nucleus. Once in the nucleus, activated ERK5 phosphorylates various target proteins, including transcription factors like MEF2C, c-Fos, and c-Myc. ERK5’s unique C-terminal transcriptional activation domain also allows it to directly control gene transcription through autophosphorylation, a mechanism distinct from other MAPKs that signal primarily through substrate phosphorylation.
ERK5’s Impact on Cells
ERK5 regulates fundamental cellular activities, including cell proliferation, differentiation, and survival. Its activation promotes cell growth and division by influencing genes such as cyclin D1, involved in cell cycle progression. ERK5 also supports cell survival by influencing proteins like BAD and FoxO3A, preventing programmed cell death.
The protein influences cellular specialization, or differentiation, by phosphorylating and activating transcription factors like MEF2 family members (MEF2A, MEF2C, and MEF2D). For instance, ERK5 interacts with MEF2C, enhancing its ability to activate genes involved in muscle cell differentiation. ERK5’s activation of transcription factors like Sap1 and c-Fos also promotes cell growth.
ERK5 in Physiology and Disease
ERK5 is involved in various biological processes. It contributes to neuronal development and survival, as neurotrophic factors can activate ERK5. In the cardiovascular system, ERK5 is involved in heart development, blood vessel maturation, and maintaining endothelial integrity; its absence leads to embryonic lethality in mice due to severe vascular defects. The MEK5-ERK5 pathway also regulates cardiac metabolism and can protect against heart failure under stress conditions.
Dysregulation of ERK5 signaling can contribute to various diseases. In cancer, aberrant ERK5 activity is observed and can promote tumor growth, metastasis, and resistance to therapies. For example, ERK5 can inhibit tumor suppressor proteins like PML, promoting cell growth. ERK5 also plays a role in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where it is involved in neuroinflammation and neuronal survival mechanisms.