How do growth factors stimulate cell division?

During the cell cycle, cell division would be affected by various division inhibitors and stimulators. Growth factors like EGF and PDGF are the primary family cell division stimulators. Growth factors or mitogen substances increase cell proliferation via several signaling pathways, which are controlled by other genes, such as proto-oncogenes and tumor suppressor genes. We’ll discuss how growth factors affect the cell cycle and how they drive cell proliferation.

G-Protein Coupled Receptor Pathway

Type G_salpha

Growth factors bind to GPCRs linked to G_s protein. This stimulates G_salpha, which then activates adenylate cyclase (AC). Adenylate cyclase converts ATP to cyclic AMP. cAMP actives protein kinase A (PKA), which affects transcription factors that increase transcription of the proto-oncogenes. Proto-oncogenes transcription moves the cell from the G1 phase to the S phase.

Type G_qalpha

The G-Protein Coupled Receptor Pathway involves growth factors binding to GPCRs, especially those containing G_q protein. This activates G_q, which stimulates phospholipase C. Phospholipase C transforms PIP2 to DAG and IP3. DAG promotes protein kinase C (PKC), which activates transcription factors or other enzymes that stimulate proto-oncogenes. IP3 releases calcium, which binds to calmodulin. The calcium-calmodulin complex activates kinases, which then trigger transcription factors or enzymes involved in proliferation activation.

Tyrosine Kinase Receptor Pathway

Growth factors bind to tyrosine kinase receptors, causing dimerization and phosphorylation of tyrosine residues. This activates the Grb-2 protein, which then activates the SOS protein. The SOS activates Ras, a GTPase. Activated Ras activates Raf, which then activates a cascade of kinases, leading to the activation of transcription factors that move to the nucleus and induce TF-2, which stimulates cycling and CDK genes. Binding cycling and CDK together release E2F from RB protein. E2F induces Proto-oncogenes transcription and moves cells from The G1 phase to the S phase of the cell cycle.

Janus Kinase Receptor Pathway

Growth factors bind to Janus kinase receptors, causing dimerization and phosphorylation of tyrosine residues. This recruits the inactive STAT proteins, and then its tyrosine residue is phosphorylated through JAK-mediated phosphorylation. Active STAT proteins move to nuclear, leading to the activation of transcription factors that move to the nucleus and induce TF-2, which stimulates cycling and CDK genes. Binding cycling and CDK together release E2F from RB protein. E2F induces Proto-oncogenes transcription and moves cells from The G1 phase to the S phase of the cell cycle.

In conclusion, Growth factors trigger cell proliferation in various cellular signaling pathways, such as the G-protein-coupled Receptor (Gsalpha and Gqalpha), the Tyrosine Kinase Receptor, and the Janus Kinase Receptor Pathway. The commonality between these pathways is that growth factors activate a transcription factor. TF moves to the nucleus, promotes some gene transcription, and ultimately drives cell proliferation.

Reference:

1. Franke, T. F. (2008). PI3K/Akt: Getting it right matters. Oncogene, 27(50), 6473–6488. https://doi.org/10.1038/onc.2008.313
2. Dhillon, A. S., Hagan, S., Rath, O., & Kolch, W. (2007). MAP kinase signaling pathways in cancer. Oncogene, 26(22), 3279–3290. https://doi.org/10.1038/sj.onc.1210421
3. Abbas et al Cell Mol Imm 2015 Elsevier
4. Figel, S., & Fenstermaker, R. A. (2018). Cell-Cycle Regulation. In Elsevier eBooks (pp. 257–269). https://doi.org/10.1016/b978-0-12-812100-9.00018-8
5. Biorender.com