Alright. So here in this video, we're going to introduce the steps in the JAK-STAT signaling pathway. And so the JAK-STAT signaling pathway really occurs in just 7 steps, as you can see down below by the seven numbers that we have here in our text. And of course, the seven numbers that we have here in our text correspond with the seven numbers that we have down below throughout our image. And so notice that step number 1 is at the top left of our image, then we make our way to the right downwards and then back to the left, and we end with step number 7 over here on the left-hand side. And so if we take a look at the very first step of the JAK-STAT signaling pathway, of course, we know from our last lesson video that cytokines such as erythropoietin or EPO will signal via the JAK-STAT pathway, and so it's no surprise that EPO here is going to act as the ligand and bind to the cytokine receptor, and this is going to cause the cytokine receptor to dimerize. And so if we take a look at step number 1 down below in our image, notice that up here at the top left, what we have is the erythropoietin molecule, the ligand here, EPO. And EPO is going to bind to the cytokine receptor, which is going to exist as these separate monomers. And in step number 1, when the ligand binds, it causes the dimerization of the cytokine monomers. And so we know that dimerization is a step that's involved with many RTKs or receptor tyrosine kinases, and this is a variation of a receptor tyrosine kinase. So notice that, down here in the cytosolic domain, there really isn't any bulky part of this cytosolic domain that can act as a Tyrosine Kinase domain. So it actually lacks Tyrosine Kinase domains. However, it's still capable of recruiting separately, separate cytosolic and soluble, Tyrosine Kinases such as JAK 2. And so this leads us directly into step number 2 of this pathway, which is that the dimerized cytokine receptor is capable of recruiting and noncovalently recruiting and activating a JAK 2, enzyme, Tyrosine Kinase Enzyme. And so if we take a look at our image down below at step number 2, notice that a separate cytosolic tyrosine kinase, called JAK 2, can be recruited by the dimerized, ligand-bound cytokine receptor. And so over here, notice that we have JAK 2, specifically 2 JAK 2 tyrosine kinases that are noncovalently recruited. And really this noncovalent recruitment is what distinguishes it from the other Tyrosine Receptor Kinases that we had seen, in our previous lesson videos. And so now we have these, JAK 2 molecules that are activated, which we can tell by the yellow borders that are around them. And so this leads us into step number 3. And in step number 3, the activated JAK 2 Tyrosine Kinases are going to do what they do, which is phosphorylate their substrate. And more specifically, the substrate is going to be the cytokine receptor. And so when the cytokine receptor gets phosphorylated by the active JAK 2 Tyrosine Kinases, this is a process that resembles autophosphorylation. Now it's not quite autophosphorylation because the receptor is not phosphorylating itself. Instead, again, there was the recruitment of a separate cytosolic tyrosine kinase that does the phosphorylation. And so that's why it's not quite autophosphorylation but it does resemble autophosphorylation. And so if we take a look at our step number 3 down below, notice that the EPO ligand-bound cytokine receptor that recruited the active JAK 2 Tyrosine Kinases has now been phosphorylated on these specific tyrosine residues. And again, that's because JAK 2 is a Tyrosine Kinase, and so it's phosphorylating Tyrosine residues. And so this leads us into step number 4. And in step number 4, the SH2 domain of a protein called STAT 5, which is just a STAT protein that we introduced in our previous lesson videos with a number 5, because there are a bunch of different STAT transcription factors. This is specifically STAT 5 that we're looking at here. And so the SH2 domain of STAT 5 is going to bind to the phosphorylated cytokine receptor. And so, of course, we know that SH2 domains bind to phosphorylated tyrosine residues, so they're going to bind to phosphorylated tyrosine residues on the cytokine receptor. And so if we take a look at our image down below at step number 4, notice that upon phosphorylation of the cytokine receptor, this is going to recruit the STAT 5 transcription factors. And so notice that the STAT 5 transcription factors have an SH2 domain, which allows it to bind to phosphorylated tyrosine residues. And so you can see that the phosphorylated tyrosine residue on the cytokine receptor is acting as the binding site for the SH2 domain of STAT 5. And notice that it's binding to STAT fives here as we can see. And this is bringing, again, the STAT 5 proteins, in very close proximity to JAK 2. And so this means that JAK 2 will now be able to act on these STAT 5 proteins. So this leads us to our step number 5. And so in step number 5, now that STAT 5 is in closer proximity to JAK, JAK 2 can now phosphorylate STAT 5. And so if we take a look at our image down below at step number 5, notice that in step number 5, we have these phosphorylated STAT 5 proteins, that were phosphorylated by JAK 2, and they have been now released from the, cytokine receptor. And so this leads us to step number 6. And in step number 6, the phosphorylated STAT 5 proteins are going to dimerize. They're going to dimerize, with another phosphorylated STAT 5. And so notice that in step number 6, down below, that these 2 STAT 5 phosphorylated proteins, are going to dimerize. So we have the dimerization of the phosphorylated STAT 5 proteins. And so now over here, you can see that we have the dimerized, STAT 5 transcription factors. And so this leads us to step number 7, our last step. And in step number 7, the, dimerized STAT 5, the STAT 5 dimerization, is going to expose a signal that ultimately transports the dimerized STAT fives into the nucleus of the cell. And once it's in the nucleus of the cell, it's capable of functioning as a transcription factor to affect genes, that ultimately lead to hematopoiesis or the formation of red blood cells. And so if we take a look at our step number 7 down below over here, notice that upon dimerization of the phosphorylated STAT 5 proteins, they're capable of making their way into the nucleus of the cell, which we're showing down here. And notice that here we're showing the dimerized STAT 5 molecules acting as a transcription factor. So they're able to perform, transcriptional, regulation of genes, again, that are going to affect cell growth, more specifically, cell growth of red blood cells in the process of hematopoiesis. And so this here concludes our introduction to the JAK-STAT pathway and its 7 steps. And moving forward, we'll be able to get some practice applying the concepts that we've learned here. So I'll see you guys in our next video.
