Other signal transduction pathways

Signal transduction allows cells to receive, interpret and respond to signals – whether external signals originating from neighboring cells, environmental factors or internal signals. Their often tightly regulated cascades enable cellular communication, direct development and maintenance of tissues and organs, control basic cellular processes like cell growth and death, respond to attacks by foreign invaders and more.

Second messengers: Amplifying cellular signals for precise response

While the particulars of each signal transduction pathway are unique, they often share certain component types. Most start with a signal, often a neurotransmitter, growth factor or hormone, activating a receptor that triggers a cascade of events. Some pathways utilize second messengers, small intracellular molecules, to transmit and amplify the signal. Calcium (Ca²⁺) is a common second messenger. In response to a signal, pumps and channels at the membrane transport Ca ²⁺ into the cell. As it accumulates, Ca ²⁺ facilitates binding by calcium-sensing proteins such as calmodulin (CaM), which results in regulation of downstream proteins, particularly those involved in muscle contraction (1). Other common second messengers include cAMP, cGMP, diacylglycerol (DAG) and inositol trisphosphate (IP₃).

Less common second messengers include nitric oxide (NO), a free radical produced by eNOS signaling. A ubiquitously expressed, calcium-dependent isoform of nitric oxide synthase (NOS), eNOS catalyzes the conversion of L-Citruline to L-Arginine to produce NO, which has effects on blood pressure, blood vessel dilation and more (2).

Kinases and scaffolding proteins: Central players in signal transmission and amplification

Another common component for transmitting and amplifying the signal are kinases, including both tyrosine kinases and serine/threonine kinases. One example is the Tec kinases, a family of non-receptor protein tyrosine kinases (PTKs) expressed predominately in hematopoietic cells. Tec kinase signaling acts downstream of cytokine- and antigen-stimulated receptors, as well as GPCRs and integrins, exerting effects on a wide variety of processes including development of the hematopoietic system, immune response, cell adhesion and migration and more (3).

Kinases and their targets are often stabilized by adaptor and scaffolding proteins that act as signaling hubs. In the case of serine-threonine kinases, the 14-3-3 family of proteins often plays that role. As highly adaptable hubs, 14-3-3 mediated signaling plays a critical role in a wide range of cellular processes, acting as an inhibitor, activator, structural stabilizer or translocation aid depending on the situation (4).

Transcription factors: The ultimate targets in cellular signal transduction

Regardless of the mechanism of signal amplification, the ultimate target of signal transduction is often transcription factors and their regulated genes. While there are many different families of transcription factors, HIF1 and NF-κB provide two examples. HIF1 is a heterodimer composed of HIF1α and HIF1-β. While HIF1-β is constitutively expressed, HIF1α accumulates under hypoxic conditions. In response to low oxygen levels, HIF1α is regulated by multiple pathways including the PI3K/AKT, PKA and MAPK/ERK pathways, affecting its stability, inhibiting its degradation and promoting its accumulation, which drives expression of HIF1 target genes (5).

In inflamed tissue, hypoxia signaling and HIF1 activation can both promote and inhibit immune system activity, depending on the cell type and context (5). One of the targets is the NF-κB pathway. Nuclear factor kappa B (NF-κB) transcription factors are hetero or homodimers composed of five known subunits: RELA/p65, c-REL, RELB, p50 and p52. Inactive NF-κB resides in the cytoplasm, bound by IκB. In response to a wide variety of stress-inducing extracellular stimuli, IκB becomes phosphorylated and targeted for degradation, freeing NF-κB to translocate to the nucleus and bind to DNA, activating gene targets involved in inflammatory response.

Different signals produce diverse effects in cell fate and development

Many distinct pathways driving cell fate and development have been described. A few examples include the following:

• Notch signaling: A developmental signaling pathway that regulates cell fate choice. Notch is a receptor that is activated by multiple instances of cleavage. The last cleavage event frees the intracellular portion, allowing it to translocate to the nucleus where it acts with other DNA-binding proteins to regulate the hair/enhancer of split (HES) and HES-related protein (HERP) transcriptional repressors (6).
• Sonic hedgehog signaling: The sonic hedgehog homolog (SHH) pathway is another developmental pathway that specifies cell fate and patterning. Secretion of SHH triggers a cascade that leads to regulation of transcription by the GLI family of transcription factors (7).
• HIPPO signaling: A developmental pathway that controls organ development and size. It acts through a tyrosine kinase cascade to phosphorylate transcription factors YAP and TAZ, blocking their translocation to the nucleus and therefore access to genes that promote cell proliferation and inhibit apoptosis (8).

Netrin signaling provides an example of signaling pathway activities that extend beyond cell fate and early development. Netrin is one of several secreted guidance cues that provide directional information to migrating neurons, attracting some axons while repelling others (9). When netrin acts solely through the DCC (Deleted in Colorectal Cancer) family of receptors without UNC-5, it has an attractive effect, with activation of DCC triggering cAMP-dependent signaling that enhances calcium channel activity leading to an influx of Ca²⁺. But when UNC5 binds to DCC, the activated complex triggers cGMP signaling that decreases Ca²⁺ currents, leading to repulsion of growth cones.

Other pathways have highly specific effects on specific cell types, as demonstrated by the impact of PEDF signaling on neurons. Pigment epithelium derived factor (PEDF) signaling protects against glutamate excitotoxicity in cerebellar granule neurons, promoting their survival by activating the NF-κB signaling pathway discussed above. PEDF is also involved in retinal neuron survival (10).

References

1. Yang C, Tsai W. Calmodulin: The switch button of calcium signaling. Tzu Chi Med J. 2021;34(1):15–22.
2. Lundberg J, Weitzberg E. Nitric oxide signaling in health and disease. Cell. 2022;185(16):2853–2878.
3. Yin Z, Zou Y, Wang D, Huang X, Xiong S, et al. Regulation of the Tec family of non-receptor tyrosine kinases in cardiovascular disease. Cell Death Discov. 2022;8(1):119.
4. Pennington KL, Chan TY, Torres MP, Andersen JL. The dynamic and stress-adaptive signaling hub of 14-3-3: Emerging mechanisms of regulation and context-dependent protein-protein interactions. Oncogene. 2018;37(42):5587–5604.
5. Corrado C, Fontana S. Hypoxia and HIF signaling: One axis with divergent effects. Int J Mol Sci. 2020;21(16):5611.
6. Zhou B, Lin W, Long Y, Yang Y, Zhang H, et al. Notch signaling pathway: Architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022;7(1):95.
7. Jing J, Wu Z, Wang J, Luo G, Lin H, et al. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies. Signal Transduct Target Ther. 2023;8(1):315.
8. Zheng Y, Pan D. The Hippo signaling pathway in development and disease. Dev Cell. 2019;50(3):264–282.
9. Boyer MP, Gupton SL. Revisiting Netrin-1: One who guides (axons). Front Cell Neurosci. 2018;12:221.
10. Bürger S,  Meng J, Zwanzig A, Beck M, Pankonin M, et al. Pigment epithelium-derived factor (PEDF) receptors are involved in survival of retinal neurons. Int J Mol Sci. 2020;22(1):369.